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Database: UniProt
Entry: Q15465
LinkDB: Q15465
Original site: Q15465 
ID   SHH_HUMAN               Reviewed;         462 AA.
AC   Q15465; A4D247; Q75MC9;
DT   15-JUL-1999, integrated into UniProtKB/Swiss-Prot.
DT   01-NOV-1996, sequence version 1.
DT   29-SEP-2021, entry version 233.
DE   RecName: Full=Sonic hedgehog protein;
DE            Short=SHH;
DE   AltName: Full=HHG-1;
DE   AltName: Full=Shh unprocessed N-terminal signaling and C-terminal autoprocessing domains {ECO:0000303|PubMed:24522195};
DE            Short=ShhNC {ECO:0000303|PubMed:24522195};
DE   Contains:
DE     RecName: Full=Sonic hedgehog protein N-product;
DE              Short=ShhN;
DE     AltName: Full=Shh N-terminal processed signaling domains {ECO:0000303|PubMed:24522195};
DE              Short=ShhNp {ECO:0000303|PubMed:24522195};
DE   Flags: Precursor;
GN   Name=SHH {ECO:0000312|HGNC:HGNC:10848};
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RC   TISSUE=Fetal lung;
RX   PubMed=7590746; DOI=10.1006/geno.1995.1104;
RA   Marigo V., Roberts D.J., Lee S.M.K., Tsukurov O., Levi T., Gastier J.M.,
RA   Epstein D.J., Gilbert D.J., Copeland N.G., Seidman C.E., Jenkins N.A.,
RA   Seidman J.G., McMahon A.P., Tabin C.;
RT   "Cloning, expression, and chromosomal location of SHH and IHH: two human
RT   homologues of the Drosophila segment polarity gene hedgehog.";
RL   Genomics 28:44-51(1995).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RA   Tate G., Kishimoto K., Mitsuya T.;
RT   "Expression of Sonic hedgehog and its receptor Patched/Smoothened in human
RT   cancer cell lines and embryonic organs.";
RL   J. Biochem. Mol. Biol. Biophys. 4:27-34(2000).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG   NIEHS SNPs program;
RL   Submitted (SEP-2003) to the EMBL/GenBank/DDBJ databases.
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=12853948; DOI=10.1038/nature01782;
RA   Hillier L.W., Fulton R.S., Fulton L.A., Graves T.A., Pepin K.H.,
RA   Wagner-McPherson C., Layman D., Maas J., Jaeger S., Walker R., Wylie K.,
RA   Sekhon M., Becker M.C., O'Laughlin M.D., Schaller M.E., Fewell G.A.,
RA   Delehaunty K.D., Miner T.L., Nash W.E., Cordes M., Du H., Sun H.,
RA   Edwards J., Bradshaw-Cordum H., Ali J., Andrews S., Isak A., Vanbrunt A.,
RA   Nguyen C., Du F., Lamar B., Courtney L., Kalicki J., Ozersky P.,
RA   Bielicki L., Scott K., Holmes A., Harkins R., Harris A., Strong C.M.,
RA   Hou S., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Leonard S.,
RA   Rohlfing T., Rock S.M., Tin-Wollam A.-M., Abbott A., Minx P., Maupin R.,
RA   Strowmatt C., Latreille P., Miller N., Johnson D., Murray J.,
RA   Woessner J.P., Wendl M.C., Yang S.-P., Schultz B.R., Wallis J.W.,
RA   Spieth J., Bieri T.A., Nelson J.O., Berkowicz N., Wohldmann P.E.,
RA   Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Bedell J.A.,
RA   Mardis E.R., Clifton S.W., Chissoe S.L., Marra M.A., Raymond C., Haugen E.,
RA   Gillett W., Zhou Y., James R., Phelps K., Iadanoto S., Bubb K., Simms E.,
RA   Levy R., Clendenning J., Kaul R., Kent W.J., Furey T.S., Baertsch R.A.,
RA   Brent M.R., Keibler E., Flicek P., Bork P., Suyama M., Bailey J.A.,
RA   Portnoy M.E., Torrents D., Chinwalla A.T., Gish W.R., Eddy S.R.,
RA   McPherson J.D., Olson M.V., Eichler E.E., Green E.D., Waterston R.H.,
RA   Wilson R.K.;
RT   "The DNA sequence of human chromosome 7.";
RL   Nature 424:157-164(2003).
RN   [5]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=12690205; DOI=10.1126/science.1083423;
RA   Scherer S.W., Cheung J., MacDonald J.R., Osborne L.R., Nakabayashi K.,
RA   Herbrick J.-A., Carson A.R., Parker-Katiraee L., Skaug J., Khaja R.,
RA   Zhang J., Hudek A.K., Li M., Haddad M., Duggan G.E., Fernandez B.A.,
RA   Kanematsu E., Gentles S., Christopoulos C.C., Choufani S., Kwasnicka D.,
RA   Zheng X.H., Lai Z., Nusskern D.R., Zhang Q., Gu Z., Lu F., Zeesman S.,
RA   Nowaczyk M.J., Teshima I., Chitayat D., Shuman C., Weksberg R.,
RA   Zackai E.H., Grebe T.A., Cox S.R., Kirkpatrick S.J., Rahman N.,
RA   Friedman J.M., Heng H.H.Q., Pelicci P.G., Lo-Coco F., Belloni E.,
RA   Shaffer L.G., Pober B., Morton C.C., Gusella J.F., Bruns G.A.P., Korf B.R.,
RA   Quade B.J., Ligon A.H., Ferguson H., Higgins A.W., Leach N.T.,
RA   Herrick S.R., Lemyre E., Farra C.G., Kim H.-G., Summers A.M., Gripp K.W.,
RA   Roberts W., Szatmari P., Winsor E.J.T., Grzeschik K.-H., Teebi A.,
RA   Minassian B.A., Kere J., Armengol L., Pujana M.A., Estivill X.,
RA   Wilson M.D., Koop B.F., Tosi S., Moore G.E., Boright A.P., Zlotorynski E.,
RA   Kerem B., Kroisel P.M., Petek E., Oscier D.G., Mould S.J., Doehner H.,
RA   Doehner K., Rommens J.M., Vincent J.B., Venter J.C., Li P.W., Mural R.J.,
RA   Adams M.D., Tsui L.-C.;
RT   "Human chromosome 7: DNA sequence and biology.";
RL   Science 300:767-772(2003).
RN   [6]
RP   PROTEIN SEQUENCE OF 24-32, PALMITOYLATION AT CYS-24, CHOLESTERYLATION,
RP   MUTAGENESIS OF CYS-24, AND MASS SPECTROMETRY.
RX   PubMed=9593755; DOI=10.1074/jbc.273.22.14037;
RA   Pepinsky R.B., Zeng C., Wen D., Rayhorn P., Baker D.P., Williams K.P.,
RA   Bixler S.A., Ambrose C.M., Garber E.A., Miatkowski K., Taylor F.R.,
RA   Wang E.A., Galdes A.;
RT   "Identification of a palmitic acid-modified form of human Sonic hedgehog.";
RL   J. Biol. Chem. 273:14037-14045(1998).
RN   [7]
RP   NUCLEOTIDE SEQUENCE [MRNA] OF 119-167.
RX   PubMed=7720571;
RA   Chang D.T., Lopez A., von Kessler D.P., Chiang C., Simandl B.K., Zhao R.,
RA   Seldin M.F., Fallon J.F., Beachy P.A.;
RT   "Products, genetic linkage and limb patterning activity of a murine
RT   hedgehog gene.";
RL   Development 120:3339-3353(1994).
RN   [8]
RP   INVOLVEMENT IN TPTPS, AND INVOLVEMENT IN PPD2.
RX   PubMed=12837695; DOI=10.1093/hmg/ddg180;
RA   Lettice L.A., Heaney S.J.H., Purdie L.A., Li L., de Beer P., Oostra B.A.,
RA   Goode D., Elgar G., Hill R.E., de Graaff E.;
RT   "A long-range Shh enhancer regulates expression in the developing limb and
RT   fin and is associated with preaxial polydactyly.";
RL   Hum. Mol. Genet. 12:1725-1735(2003).
RN   [9]
RP   GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-278.
RC   TISSUE=Plasma;
RX   PubMed=16335952; DOI=10.1021/pr0502065;
RA   Liu T., Qian W.-J., Gritsenko M.A., Camp D.G. II, Monroe M.E., Moore R.J.,
RA   Smith R.D.;
RT   "Human plasma N-glycoproteome analysis by immunoaffinity subtraction,
RT   hydrazide chemistry, and mass spectrometry.";
RL   J. Proteome Res. 4:2070-2080(2005).
RN   [10]
RP   PALMITOYLATION AT CYS-24, MUTAGENESIS OF CYS-24, AND SUBCELLULAR LOCATION.
RX   PubMed=18534984; DOI=10.1074/jbc.m803901200;
RA   Buglino J.A., Resh M.D.;
RT   "Hhat is a palmitoylacyltransferase with specificity for N-palmitoylation
RT   of Sonic Hedgehog.";
RL   J. Biol. Chem. 283:22076-22088(2008).
RN   [11]
RP   INVOLVEMENT IN TPTPS.
RX   PubMed=18417549; DOI=10.1136/jmg.2008.057646;
RA   Sun M., Ma F., Zeng X., Liu Q., Zhao X.-L., Wu F.-X., Wu G.-P.,
RA   Zhang Z.-F., Gu B., Zhao Y.-F., Tian S.-H., Lin B., Kong X.-Y.,
RA   Zhang X.-L., Yang W., Lo W.H.-Y., Zhang X.;
RT   "Triphalangeal thumb-polysyndactyly syndrome and syndactyly type IV are
RT   caused by genomic duplications involving the long range, limb-specific SHH
RT   enhancer.";
RL   J. Med. Genet. 45:589-595(2008).
RN   [12]
RP   INVOLVEMENT IN THYP.
RX   PubMed=19847792; DOI=10.1002/humu.21142;
RA   Wieczorek D., Pawlik B., Li Y., Akarsu N.A., Caliebe A., May K.J.,
RA   Schweiger B., Vargas F.R., Balci S., Gillessen-Kaesbach G., Wollnik B.;
RT   "A specific mutation in the distant sonic hedgehog (SHH) cis-regulator
RT   (ZRS) causes Werner mesomelic syndrome (WMS) while complete ZRS
RT   duplications underlie Haas type polysyndactyly and preaxial polydactyly
RT   (PPD) with or without triphalangeal thumb.";
RL   Hum. Mutat. 31:81-89(2010).
RN   [13]
RP   INTERACTION WITH DISP1 AND SCUBE2, SUBUNIT, AND CAUTION.
RX   PubMed=22902404; DOI=10.1016/j.celrep.2012.07.010;
RA   Tukachinsky H., Kuzmickas R.P., Jao C.Y., Liu J., Salic A.;
RT   "Dispatched and scube mediate the efficient secretion of the cholesterol-
RT   modified hedgehog ligand.";
RL   Cell Rep. 2:308-320(2012).
RN   [14]
RP   PALMITOYLATION AT CYS-24, AND MUTAGENESIS OF CYS-24.
RX   PubMed=31875564; DOI=10.1016/j.celrep.2019.11.110;
RA   Asciolla J.J., Resh M.D.;
RT   "Hedgehog Acyltransferase Promotes Uptake of Palmitoyl-CoA across the
RT   Endoplasmic Reticulum Membrane.";
RL   Cell Rep. 29:4608-4619(2019).
RN   [15]
RP   INTERACTION WITH SCUBE2, SUBUNIT, AND CAUTION.
RX   PubMed=22677548; DOI=10.1101/gad.191866.112;
RA   Creanga A., Glenn T.D., Mann R.K., Saunders A.M., Talbot W.S., Beachy P.A.;
RT   "Scube/You activity mediates release of dually lipid-modified Hedgehog
RT   signal in soluble form.";
RL   Genes Dev. 26:1312-1325(2012).
RN   [16]
RP   PTM, AND DOMAIN.
RX   PubMed=23118222; DOI=10.1074/jbc.m112.356667;
RA   Ohlig S., Pickhinke U., Sirko S., Bandari S., Hoffmann D., Dreier R.,
RA   Farshi P., Goetz M., Grobe K.;
RT   "An emerging role of Sonic hedgehog shedding as a modulator of heparan
RT   sulfate interactions.";
RL   J. Biol. Chem. 287:43708-43719(2012).
RN   [17]
RP   REVIEW.
RX   PubMed=23154980; DOI=10.1101/gad.207126.112;
RA   Ingham P.W.;
RT   "Zebrafish genetics gets the Scube on Hedgehog secretion.";
RL   Genes Dev. 26:2468-2470(2012).
RN   [18]
RP   PTM, INTERACTION WITH SCUBE2, SUBUNIT, SUBCELLULAR LOCATION, FUNCTION, AND
RP   CAUTION.
RX   PubMed=24522195; DOI=10.1242/jcs.137695;
RA   Jakobs P., Exner S., Schuermann S., Pickhinke U., Bandari S., Ortmann C.,
RA   Kupich S., Schulz P., Hansen U., Seidler D.G., Grobe K.;
RT   "Scube2 enhances proteolytic Shh processing from the surface of Shh-
RT   producing cells.";
RL   J. Cell Sci. 127:1726-1737(2014).
RN   [19]
RP   INVOLVEMENT IN LSS.
RX   PubMed=24456159; DOI=10.1111/cge.12352;
RA   Lohan S., Spielmann M., Doelken S.C., Floettmann R., Muhammad F.,
RA   Baig S.M., Wajid M., Huelsemann W., Habenicht R., Kjaer K.W., Patil S.J.,
RA   Girisha K.M., Abarca-Barriga H.H., Mundlos S., Klopocki E.;
RT   "Microduplications encompassing the Sonic hedgehog limb enhancer ZRS are
RT   associated with Haas-type polysyndactyly and Laurin-Sandrow syndrome.";
RL   Clin. Genet. 86:318-325(2014).
RN   [20]
RP   INVOLVEMENT IN THYP.
RX   PubMed=24965254; DOI=10.1038/jhg.2014.50;
RA   Norbnop P., Srichomthong C., Suphapeetiporn K., Shotelersuk V.;
RT   "ZRS 406A>G mutation in patients with tibial hypoplasia, polydactyly and
RT   triphalangeal first fingers.";
RL   J. Hum. Genet. 59:467-470(2014).
RN   [21]
RP   REVIEW, AND FUNCTION.
RX   PubMed=24863049; DOI=10.1002/dneu.22193;
RA   Pal K., Mukhopadhyay S.;
RT   "Primary cilium and sonic hedgehog signaling during neural tube patterning:
RT   role of GPCRs and second messengers.";
RL   Dev. Neurobiol. 75:337-348(2015).
RN   [22]
RP   REVIEW, CAUTION, SUBCELLULAR LOCATION, AND PTM.
RX   PubMed=26875496; DOI=10.1016/j.ydbio.2016.02.009;
RA   Xavier G.M., Seppala M., Barrell W., Birjandi A.A., Geoghegan F.,
RA   Cobourne M.T.;
RT   "Hedgehog receptor function during craniofacial development.";
RL   Dev. Biol. 415:198-215(2016).
RN   [23]
RP   X-RAY CRYSTALLOGRAPHY (1.85 ANGSTROMS) OF 25-197 IN COMPLEX WITH ZINC IONS,
RP   FUNCTION, DOMAIN, AND SUBUNIT.
RX   PubMed=10753901; DOI=10.1074/jbc.275.15.10995;
RA   Pepinsky R.B., Rayhorn P., Day E.S., Dergay A., Williams K.P., Galdes A.,
RA   Taylor F.R., Boriack-Sjodin P.A., Garber E.A.;
RT   "Mapping sonic hedgehog-receptor interactions by steric interference.";
RL   J. Biol. Chem. 275:10995-11001(2000).
RN   [24]
RP   X-RAY CRYSTALLOGRAPHY (3.01 ANGSTROMS) OF 29-197 IN COMPLEX WITH HHIP; ZINC
RP   AND CALCIUM IONS, DOMAIN, INTERACTION WITH HHIP, AND SUBUNIT.
RX   PubMed=19561609; DOI=10.1038/nsmb.1632;
RA   Bosanac I., Maun H.R., Scales S.J., Wen X., Lingel A., Bazan J.F.,
RA   de Sauvage F.J., Hymowitz S.G., Lazarus R.A.;
RT   "The structure of SHH in complex with HHIP reveals a recognition role for
RT   the Shh pseudo active site in signaling.";
RL   Nat. Struct. Mol. Biol. 16:691-697(2009).
RN   [25]
RP   X-RAY CRYSTALLOGRAPHY (1.83 ANGSTROMS) OF 29-197 IN COMPLEX WITH MONOCLONAL
RP   ANTIBODY; ZINC AND CALCIUM IONS, AND DOMAIN.
RX   PubMed=20504762; DOI=10.1074/jbc.m110.112284;
RA   Maun H.R., Wen X., Lingel A., de Sauvage F.J., Lazarus R.A., Scales S.J.,
RA   Hymowitz S.G.;
RT   "Hedgehog pathway antagonist 5E1 binds hedgehog at the pseudo-active
RT   site.";
RL   J. Biol. Chem. 285:26570-26580(2010).
RN   [26]
RP   VARIANTS HPE3 ARG-31; GLY-117 AND ARG-117.
RX   PubMed=8896572; DOI=10.1038/ng1196-357;
RA   Roessler E., Belloni E., Gaudenz K., Jay P., Berta P., Scherer S.W.,
RA   Tsui L.-C., Muenke M.;
RT   "Mutations in the human Sonic hedgehog gene cause holoprosencephaly.";
RL   Nat. Genet. 14:357-360(1996).
RN   [27]
RP   VARIANTS HPE3 ARG-31; GLY-117; ARG-117; GLU-224; THR-226 AND THR-383.
RX   PubMed=9302262; DOI=10.1093/hmg/6.11.1847;
RA   Roessler E., Belloni E., Gaudenz K., Vargas F., Scherer S.W., Tsui L.-C.,
RA   Muenke M.;
RT   "Mutations in the C-terminal domain of Sonic hedgehog cause
RT   holoprosencephaly.";
RL   Hum. Mol. Genet. 6:1847-1853(1997).
RN   [28]
RP   VARIANTS HPE3 HIS-100; GLN-188 AND ASN-222.
RX   PubMed=10441331; DOI=10.1093/hmg/8.9.1683;
RA   Odent S., Atti-Bitach T., Blayau M., Mathieu M., Aug J., Delezo de A.L.,
RA   Gall J.Y., Le Marec B., Munnich A., David V., Vekemans M.;
RT   "Expression of the Sonic hedgehog (SHH) gene during early human development
RT   and phenotypic expression of new mutations causing holoprosencephaly.";
RL   Hum. Mol. Genet. 8:1683-1689(1999).
RN   [29]
RP   VARIANTS HPE3 VAL-88; LYS-115; ARG-236; 263-ARG--ALA-269 DEL; ASP-290;
RP   ALA-424 AND LEU-436.
RX   PubMed=10556296; DOI=10.1093/hmg/8.13.2479;
RA   Nanni L., Ming J.E., Bocian M., Steinhaus K., Bianchi D.W.,
RA   Die-Smulders C., Giannotti A., Imaizumi K., Jones K.L., Campo M.D.,
RA   Martin R.A., Meinecke P., Pierpont M.E.M., Robin N.H., Young I.D.,
RA   Roessler E., Muenke M.;
RT   "The mutational spectrum of the sonic hedgehog gene in holoprosencephaly:
RT   SHH mutations cause a significant proportion of autosomal dominant
RT   holoprosencephaly.";
RL   Hum. Mol. Genet. 8:2479-2488(1999).
RN   [30]
RP   VARIANT SMMCI PHE-111.
RX   PubMed=11471164;
RX   DOI=10.1002/1096-8628(20010722)102:1<1::aid-ajmg1336>3.0.co;2-u;
RA   Nanni L., Ming J.E., Du Y., Hall R.K., Aldred M., Bankier A., Muenke M.;
RT   "SHH mutation is associated with solitary median maxillary central incisor:
RT   a study of 13 patients and review of the literature.";
RL   Am. J. Med. Genet. 102:1-10(2001).
RN   [31]
RP   VARIANTS HPE3 PRO-140 AND PHE-183.
RX   PubMed=11479728; DOI=10.1007/s004390100537;
RA   Orioli I.M., Castilla E.E., Ming J.E., Nazer J., Burle de Aguiar M.J.,
RA   Llerena J.C., Muenke M.;
RT   "Identification of novel mutations in SHH and ZIC2 in a South American
RT   (ECLAMC) population with holoprosencephaly.";
RL   Hum. Genet. 109:1-6(2001).
RN   [32]
RP   VARIANT MCOPCB5 401-SER--GLY-408 DEL.
RX   PubMed=12503095; DOI=10.1002/ajmg.a.10884;
RA   Schimmenti L.A., de la Cruz J., Lewis R.A., Karkera J.D., Manligas G.S.,
RA   Roessler E., Muenke M.;
RT   "Novel mutation in sonic hedgehog in non-syndromic colobomatous
RT   microphthalmia.";
RL   Am. J. Med. Genet. A 116:215-221(2003).
RN   [33]
RP   VARIANT SMMCI ALA-332.
RX   PubMed=15103725; DOI=10.1002/ajmg.a.20685;
RA   Garavelli L., Zanacca C., Caselli G., Banchini G., Dubourg C., David V.,
RA   Odent S., Gurrieri F., Neri G.;
RT   "Solitary median maxillary central incisor syndrome: clinical case with a
RT   novel mutation of sonic hedgehog.";
RL   Am. J. Med. Genet. A 127:93-95(2004).
RN   [34]
RP   VARIANTS HPE3 ALA-27; ILE-267 AND THR-373.
RX   PubMed=15107988; DOI=10.1007/s00431-004-1459-0;
RA   Hehr U., Gross C., Diebold U., Wahl D., Beudt U., Heidemann P., Hehr A.,
RA   Mueller D.;
RT   "Wide phenotypic variability in families with holoprosencephaly and a sonic
RT   hedgehog mutation.";
RL   Eur. J. Pediatr. 163:347-352(2004).
RN   [35]
RP   VARIANTS HPE3 THR-6; HIS-100; 106-LEU-ASN-107 DEL; ASP-110; ARG-150;
RP   176-GLU--LYS-178 DEL; GLN-188; ASN-222; PRO-271; ALA-332; GLN-347; THR-354
RP   AND PRO-381.
RX   PubMed=15221788; DOI=10.1002/humu.20056;
RA   Dubourg C., Lazaro L., Pasquier L., Bendavid C., Blayau M., Le Duff F.,
RA   Durou M.-R., Odent S., David V.;
RT   "Molecular screening of SHH, ZIC2, SIX3, and TGIF genes in patients with
RT   features of holoprosencephaly spectrum: mutation review and genotype-
RT   phenotype correlations.";
RL   Hum. Mutat. 24:43-51(2004).
RN   [36]
RP   VARIANT HPE3 ASN-111.
RX   PubMed=15942952; DOI=10.1002/ajmg.a.30624;
RA   El-Jaick K.B., Brunoni D., Castilla E.E., Moreira M.A., Orioli I.M.;
RT   "SHH Ile111Asp in alobar holoprosencephaly in a proposita, whose mother had
RT   only a solitary median maxillary incisor.";
RL   Am. J. Med. Genet. A 136:345-345(2005).
RN   [37]
RP   VARIANT HPE3 GLN-140.
RX   PubMed=15942953; DOI=10.1002/ajmg.a.30625;
RA   Ribeiro L.A., Richieri-Costa A.;
RT   "Single median maxillary central incisor, hypophyseal tumor, and SHH
RT   mutation.";
RL   Am. J. Med. Genet. A 136:346-347(2005).
RN   [38]
RP   CHARACTERIZATION OF VARIANTS HPE3 ARG-31; VAL-88; HIS-100; LYS-115;
RP   ARG-117; GLY-117 AND GLN-188.
RX   PubMed=16282375; DOI=10.1073/pnas.0507848102;
RA   Maity T., Fuse N., Beachy P.A.;
RT   "Molecular mechanisms of Sonic hedgehog mutant effects in
RT   holoprosencephaly.";
RL   Proc. Natl. Acad. Sci. U.S.A. 102:17026-17031(2005).
RN   [39]
RP   VARIANTS HPE3 GLN-140; PRO-218 AND TYR-363.
RX   PubMed=17001669; DOI=10.1002/ajmg.a.31378;
RA   Richieri-Costa A., Ribeiro L.A.;
RT   "Holoprosencephaly-like phenotype: clinical and genetic perspectives.";
RL   Am. J. Med. Genet. A 140:2587-2593(2006).
RN   [40]
RP   VARIANTS HPE3 THR-6; PRO-17; LEU-26; ALA-27; ARG-31; PRO-39; LYS-53;
RP   VAL-83; PHE-84; VAL-88; HIS-100; ARG-102; TYR-102; 106-LEU-ASN-107 DEL;
RP   PHE-109; THR-110; ASP-110; PHE-111; ASN-111; LYS-115; GLY-117; ARG-117;
RP   MET-124; LYS-136; PRO-140; GLN-140; ASP-143; PRO-144; ASN-147; ARG-150;
RP   LYS-150; ARG-156; CYS-170; HIS-171; 176-GLU--LYS-178 DEL; ARG-183; PHE-183;
RP   TYR-183; LEU-184; GLN-188; GLU-196; 196-GLY--PRO-200 DEL; VAL-197; SER-198;
RP   PHE-198; PRO-218; ASN-222; GLU-224; THR-226; VAL-231; GLY-232; PRO-234;
RP   ARG-236; ASN-236; VAL-241; LEU-241; ASN-255; 263-ARG--ALA-269 DEL; ILE-267;
RP   PRO-271; GLU-275; TRP-280; ASP-290; ALA-296; CYS-310; SER-321; ALA-332;
RP   VAL-346; ARG-347; GLN-347; LEU-347; THR-354; LEU-362; TYR-363; CYS-364;
RP   THR-373; ARG-374; ASP-376; SER-377; 378-ALA--PHE-380 DEL; PRO-381; PRO-382;
RP   THR-383; THR-391; 402-GLY--GLY-409 DEL; 405-ASP--GLY-409 DEL; GLY-411 INS;
RP   ALA-416; ALA-424; ASN-435; LEU-436 AND ARG-456.
RX   PubMed=19603532; DOI=10.1002/humu.21090;
RA   Roessler E., El-Jaick K.B., Dubourg C., Velez J.I., Solomon B.D.,
RA   Pineda-Alvarez D.E., Lacbawan F., Zhou N., Ouspenskaia M., Paulussen A.,
RA   Smeets H.J., Hehr U., Bendavid C., Bale S., Odent S., David V., Muenke M.;
RT   "The mutational spectrum of holoprosencephaly-associated changes within the
RT   SHH gene in humans predicts loss-of-function through either key structural
RT   alterations of the ligand or its altered synthesis.";
RL   Hum. Mutat. 30:E921-E935(2009).
CC   -!- FUNCTION: [Sonic hedgehog protein]: The C-terminal part of the sonic
CC       hedgehog protein precursor displays an autoproteolysis and a
CC       cholesterol transferase activity (By similarity). Both activities
CC       result in the cleavage of the full-length protein into two parts (ShhN
CC       and ShhC) followed by the covalent attachment of a cholesterol moiety
CC       to the C-terminal of the newly generated ShhN (By similarity). Both
CC       activities occur in the reticulum endoplasmic (By similarity). Once
CC       cleaved, ShhC is degraded in the endoplasmic reticulum (By similarity).
CC       {ECO:0000250|UniProtKB:Q62226}.
CC   -!- FUNCTION: [Sonic hedgehog protein N-product]: The dually lipidated
CC       sonic hedgehog protein N-product (ShhNp) is a morphogen which is
CC       essential for a variety of patterning events during development.
CC       Induces ventral cell fate in the neural tube and somites
CC       (PubMed:24863049). Involved in the patterning of the anterior-posterior
CC       axis of the developing limb bud (By similarity). Essential for axon
CC       guidance (By similarity). Binds to the patched (PTCH1) receptor, which
CC       functions in association with smoothened (SMO), to activate the
CC       transcription of target genes (PubMed:10753901). In the absence of SHH,
CC       PTCH1 represses the constitutive signaling activity of SMO
CC       (PubMed:10753901). {ECO:0000250|UniProtKB:Q62226,
CC       ECO:0000269|PubMed:10753901, ECO:0000269|PubMed:24863049,
CC       ECO:0000303|PubMed:24522195}.
CC   -!- SUBUNIT: Interacts with HHATL/GUP1 which negatively regulates HHAT-
CC       mediated palmitoylation of the SHH N-terminus (By similarity). ShhNp is
CC       active as a multimer (PubMed:24522195). Interacts with BOC and CDON (By
CC       similarity). Interacts with HHIP (PubMed:19561609). Interacts with
CC       DISP1 via its cholesterol anchor (PubMed:22902404, PubMed:22677548).
CC       Interacts with SCUBE2 (PubMed:24522195, PubMed:22677548). Interacts
CC       with glypican GPC3 (By similarity). {ECO:0000250|UniProtKB:Q62226,
CC       ECO:0000269|PubMed:19561609, ECO:0000269|PubMed:22677548,
CC       ECO:0000269|PubMed:22902404, ECO:0000269|PubMed:24522195}.
CC   -!- INTERACTION:
CC       Q15465; Q96QV1: HHIP; NbExp=10; IntAct=EBI-11666886, EBI-6598521;
CC       Q15465; Q13635: PTCH1; NbExp=2; IntAct=EBI-11666886, EBI-8775406;
CC       Q15465; Q13635-1: PTCH1; NbExp=4; IntAct=EBI-11666886, EBI-13635488;
CC   -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC       {ECO:0000305|PubMed:18534984}. Golgi apparatus membrane
CC       {ECO:0000305|PubMed:18534984}. Note=Co-localizes with HHAT in the ER
CC       and Golgi membrane. {ECO:0000305|PubMed:18534984}.
CC   -!- SUBCELLULAR LOCATION: [Sonic hedgehog protein N-product]: Cell membrane
CC       {ECO:0000250|UniProtKB:Q62226}; Lipid-anchor
CC       {ECO:0000250|UniProtKB:Q62226}. Note=The dual-lipidated sonic hedgehog
CC       protein N-product (ShhNp) is firmly tethered to the cell membrane where
CC       it forms multimers (PubMed:24522195). Further solubilization and
CC       release from the cell surface seem to be achieved through different
CC       mechanisms, including the interaction with DISP1 and SCUBE2, movement
CC       by lipoprotein particles, transport by cellular extensions called
CC       cytonemes or by the proteolytic removal of both terminal lipidated
CC       peptides (PubMed:26875496, PubMed:24522195).
CC       {ECO:0000305|PubMed:24522195, ECO:0000305|PubMed:26875496}.
CC   -!- DOMAIN: [Sonic hedgehog protein N-product]: Binds calcium and zinc
CC       ions; this stabilizes the protein fold and is essential for protein-
CC       protein interactions mediated by this domain.
CC       {ECO:0000269|PubMed:10753901, ECO:0000269|PubMed:19561609,
CC       ECO:0000269|PubMed:20504762}.
CC   -!- DOMAIN: [Sonic hedgehog protein N-product]: The Cardin-Weintraub (CW)
CC       motif is required for heparan sulfate binding of the solubilized ShhNp
CC       (PubMed:23118222). The N-terminal palmitoylated peptide is cleaved at
CC       the heparan sulfate-binding Cardin-Weintraub (CW) motif site
CC       (PubMed:24522195). The cleavage reduced the interactions with heparan
CC       sulfate. The cleavage is enhanced by SCUBE2 (PubMed:24522195).
CC       {ECO:0000269|PubMed:23118222, ECO:0000269|PubMed:24522195}.
CC   -!- PTM: [Sonic hedgehog protein]: The C-terminal domain displays an
CC       autoproteolysis activity and a cholesterol transferase activity (By
CC       similarity). Both activities result in the cleavage of the full-length
CC       protein and covalent attachment of a cholesterol moiety to the C-
CC       terminal of the newly generated N-terminal fragment (ShhN) (By
CC       similarity). Cholesterylation is required for the sonic hedgehog
CC       protein N-product targeting to lipid rafts and multimerization
CC       (PubMed:24522195, PubMed:26875496). ShhN is the active species in both
CC       local and long-range signaling, whereas the C-product (ShhC) is
CC       degraded in the reticulum endoplasmic (By similarity).
CC       {ECO:0000250|UniProtKB:Q62226, ECO:0000303|PubMed:26875496,
CC       ECO:0000305|PubMed:24522195}.
CC   -!- PTM: [Sonic hedgehog protein N-product]: N-palmitoylation by HHAT of
CC       ShhN is required for sonic hedgehog protein N-product multimerization
CC       and full activity (By similarity). It is a prerequisite for the
CC       membrane-proximal positioning and the subsequent shedding of this N-
CC       terminal peptide (PubMed:24522195). {ECO:0000250|UniProtKB:Q62226,
CC       ECO:0000269|PubMed:24522195}.
CC   -!- PTM: [Sonic hedgehog protein N-product]: The lipidated N- and C-
CC       terminal peptides of ShhNp can be cleaved (shedding)(PubMed:24522195).
CC       The N-terminal palmitoylated peptide is cleaved at the Cardin-Weintraub
CC       (CW) motif site (PubMed:24522195). The cleavage reduced the
CC       interactions with heparan sulfate. The cleavage is enhanced by SCUBE2
CC       (PubMed:24522195, PubMed:23118222). {ECO:0000269|PubMed:23118222,
CC       ECO:0000269|PubMed:24522195}.
CC   -!- MASS SPECTROMETRY: [Sonic hedgehog protein N-product]: Mass=19.560;
CC       Method=Electrospray; Note=Sonic hedgehog protein N-product: soluble
CC       product, purified from insect cells.;
CC       Evidence={ECO:0000269|PubMed:9593755};
CC   -!- MASS SPECTROMETRY: [Sonic hedgehog protein N-product]: Mass=20.167;
CC       Method=Electrospray; Note=Sonic hedgehog protein N-product: Membrane-
CC       bound product, purified from insect cells.;
CC       Evidence={ECO:0000269|PubMed:9593755};
CC   -!- DISEASE: Microphthalmia, isolated, with coloboma, 5 (MCOPCB5)
CC       [MIM:611638]: A disorder of eye formation, ranging from small size of a
CC       single eye to complete bilateral absence of ocular tissues. Ocular
CC       abnormalities like opacities of the cornea and lens, scaring of the
CC       retina and choroid, and other abnormalities may also be present. Ocular
CC       colobomas are a set of malformations resulting from abnormal
CC       morphogenesis of the optic cup and stalk, and the fusion of the fetal
CC       fissure (optic fissure). {ECO:0000269|PubMed:12503095}. Note=The
CC       disease is caused by variants affecting the gene represented in this
CC       entry.
CC   -!- DISEASE: Holoprosencephaly 3 (HPE3) [MIM:142945]: A structural anomaly
CC       of the brain, in which the developing forebrain fails to correctly
CC       separate into right and left hemispheres. Holoprosencephaly is
CC       genetically heterogeneous and associated with several distinct facies
CC       and phenotypic variability. The majority of holoprosencephaly type 3
CC       cases are apparently sporadic, although clear examples of autosomal
CC       dominant inheritance have been described. {ECO:0000269|PubMed:10441331,
CC       ECO:0000269|PubMed:10556296, ECO:0000269|PubMed:11479728,
CC       ECO:0000269|PubMed:15107988, ECO:0000269|PubMed:15221788,
CC       ECO:0000269|PubMed:15942952, ECO:0000269|PubMed:15942953,
CC       ECO:0000269|PubMed:16282375, ECO:0000269|PubMed:17001669,
CC       ECO:0000269|PubMed:19603532, ECO:0000269|PubMed:8896572,
CC       ECO:0000269|PubMed:9302262}. Note=The disease is caused by variants
CC       affecting the gene represented in this entry.
CC   -!- DISEASE: Solitary median maxillary central incisor (SMMCI)
CC       [MIM:147250]: Rare dental anomaly characterized by the congenital
CC       absence of one maxillary central incisor. {ECO:0000269|PubMed:11471164,
CC       ECO:0000269|PubMed:15103725}. Note=The disease is caused by variants
CC       affecting the gene represented in this entry.
CC   -!- DISEASE: Triphalangeal thumb-polysyndactyly syndrome (TPTPS)
CC       [MIM:174500]: Autosomal dominant syndrome. It is characterized by a
CC       wide spectrum of pre- and post-axial abnormalities due to altered SHH
CC       expression pattern during limb development.
CC       {ECO:0000269|PubMed:12837695, ECO:0000269|PubMed:18417549}. Note=The
CC       gene represented in this entry is involved in disease pathogenesis.
CC       Mutations located in intron 5 of LMBR1 disrupt a long-range, cis-
CC       regulatory element of SHH expression.
CC   -!- DISEASE: Preaxial polydactyly 2 (PPD2) [MIM:174500]: Polydactyly
CC       consists of duplication of the distal phalanx. The thumb in PPD2 is
CC       usually opposable and possesses a normal metacarpal.
CC       {ECO:0000269|PubMed:12837695}. Note=The gene represented in this entry
CC       is involved in disease pathogenesis. Mutations located in intron 5 of
CC       LMBR1 disrupt a long-range, cis-regulatory element of SHH and result in
CC       abnormal, ectopic SHH expression with pathological consequences
CC       (PubMed:12837695). {ECO:0000269|PubMed:12837695}.
CC   -!- DISEASE: Hypoplasia or aplasia of tibia with polydactyly (THYP)
CC       [MIM:188740]: An autosomal dominant disease characterized by
CC       hypoplastic or absent tibia, and polydactyly.
CC       {ECO:0000269|PubMed:19847792, ECO:0000269|PubMed:24965254}. Note=The
CC       gene represented in this entry is involved in disease pathogenesis.
CC       Mutations located in intron 5 of LMBR1 disrupt a long-range, cis-
CC       regulatory element of SHH and result in abnormal, ectopic SHH
CC       expression with pathological consequences.
CC       {ECO:0000303|PubMed:19847792, ECO:0000303|PubMed:24965254}.
CC   -!- DISEASE: Laurin-Sandrow syndrome (LSS) [MIM:135750]: A rare autosomal
CC       dominant disorder characterized by polysyndactyly of hands and/or feet,
CC       mirror image duplication of the feet, nasal defects, and loss of
CC       identity between fibula and tibia. Some patients do not have nasal
CC       abnormalities (segmental Laurin-Sandrow syndrome).
CC       {ECO:0000269|PubMed:24456159}. Note=The gene represented in this entry
CC       is involved in disease pathogenesis. Abnormal SHH limb expression with
CC       pathological consequences is caused by duplications (16-75 kb)
CC       involving the ZPA regulatory sequence (ZRS), a SHH long-range cis-
CC       regulatory element, located in LMBR1 intron 5 (PubMed:24456159).
CC   -!- SIMILARITY: Belongs to the hedgehog family. {ECO:0000305}.
CC   -!- CAUTION: The several steps and mechanisms that permit controlled Shh
CC       dispersion and gradient formation remain controversial. The ShhNC C-
CC       terminal domain displays an autoproteolysis activity and a cholesterol
CC       transferase activity resulting in the cleavage and covalent attachment
CC       of a cholesterol moiety to the C-terminal of the newly generated N-
CC       terminal fragment (ShhN). The protein is further modified by covalent
CC       addition of palmitate at the N-terminal of ShhN, resulting to the dual-
CC       lipidated Shh (ShhNp). ShhNp is firmly tethered to the cell membrane
CC       where it forms multimers. Further solubilization and release from the
CC       cell surface seem to be achieved through different mechanisms,
CC       including the interaction with DISP1 and SCUBE2, movement by
CC       lipoprotein particles, transport by cellular extensions called
CC       cytonemes or by proteolytic removal of both terminal lipidated peptides
CC       (PubMed:26875496). Once released, the fully processed Shh can signal
CC       within embryonic tissues both at short and long-range.
CC       {ECO:0000269|PubMed:24522195, ECO:0000303|PubMed:26875496,
CC       ECO:0000305|PubMed:22677548, ECO:0000305|PubMed:22902404}.
CC   -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC       Haematology;
CC       URL="http://atlasgeneticsoncology.org/Genes/SHHID378.html";
CC   -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC       URL="http://egp.gs.washington.edu/data/shh/";
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DR   EMBL; L38518; AAA62179.1; -; mRNA.
DR   EMBL; AY422195; AAQ87879.1; -; Genomic_DNA.
DR   EMBL; AC002484; AAB67604.1; -; Genomic_DNA.
DR   EMBL; AC078834; AAS01990.1; -; Genomic_DNA.
DR   EMBL; CH236954; EAL23913.1; -; Genomic_DNA.
DR   CCDS; CCDS5942.1; -.
DR   RefSeq; NP_000184.1; NM_000193.3.
DR   PDB; 3HO5; X-ray; 3.01 A; H=29-197.
DR   PDB; 3M1N; X-ray; 1.85 A; A/B=23-197.
DR   PDB; 3MXW; X-ray; 1.83 A; A=29-197.
DR   PDB; 6DMY; EM; 3.60 A; B=24-197.
DR   PDB; 6E1H; EM; 3.50 A; C=24-197.
DR   PDB; 6N7G; EM; 6.80 A; C/F=24-197.
DR   PDB; 6N7H; EM; 3.60 A; C=24-197.
DR   PDB; 6N7K; EM; 6.50 A; C/F=24-197.
DR   PDB; 6OEV; EM; 3.80 A; C=24-197.
DR   PDB; 6PJV; X-ray; 1.43 A; A=29-197.
DR   PDB; 6RMG; EM; 3.40 A; B=21-197.
DR   PDB; 6RVD; EM; 3.50 A; C=24-197.
DR   PDB; 7MHZ; EM; 3.20 A; B=24-31.
DR   PDBsum; 3HO5; -.
DR   PDBsum; 3M1N; -.
DR   PDBsum; 3MXW; -.
DR   PDBsum; 6DMY; -.
DR   PDBsum; 6E1H; -.
DR   PDBsum; 6N7G; -.
DR   PDBsum; 6N7H; -.
DR   PDBsum; 6N7K; -.
DR   PDBsum; 6OEV; -.
DR   PDBsum; 6PJV; -.
DR   PDBsum; 6RMG; -.
DR   PDBsum; 6RVD; -.
DR   PDBsum; 7MHZ; -.
DR   SMR; Q15465; -.
DR   BioGRID; 112365; 10.
DR   DIP; DIP-61763N; -.
DR   IntAct; Q15465; 3.
DR   STRING; 9606.ENSP00000297261; -.
DR   BindingDB; Q15465; -.
DR   ChEMBL; CHEMBL5602; -.
DR   DrugCentral; Q15465; -.
DR   MEROPS; C46.002; -.
DR   GlyGen; Q15465; 1 site.
DR   iPTMnet; Q15465; -.
DR   PhosphoSitePlus; Q15465; -.
DR   SwissPalm; Q15465; -.
DR   BioMuta; SHH; -.
DR   DMDM; 6094283; -.
DR   MassIVE; Q15465; -.
DR   PaxDb; Q15465; -.
DR   PeptideAtlas; Q15465; -.
DR   PRIDE; Q15465; -.
DR   ProteomicsDB; 60602; -.
DR   ABCD; Q15465; 17 sequenced antibodies.
DR   Antibodypedia; 4514; 646 antibodies.
DR   DNASU; 6469; -.
DR   Ensembl; ENST00000297261; ENSP00000297261; ENSG00000164690.
DR   GeneID; 6469; -.
DR   KEGG; hsa:6469; -.
DR   UCSC; uc003wmk.2; human.
DR   CTD; 6469; -.
DR   DisGeNET; 6469; -.
DR   GeneCards; SHH; -.
DR   GeneReviews; SHH; -.
DR   HGNC; HGNC:10848; SHH.
DR   HPA; ENSG00000164690; Tissue enhanced (gallbladder, liver).
DR   MalaCards; SHH; -.
DR   MIM; 135750; phenotype.
DR   MIM; 142945; phenotype.
DR   MIM; 147250; phenotype.
DR   MIM; 174500; phenotype.
DR   MIM; 188740; phenotype.
DR   MIM; 600725; gene.
DR   MIM; 611638; phenotype.
DR   neXtProt; NX_Q15465; -.
DR   OpenTargets; ENSG00000164690; -.
DR   Orphanet; 485275; Acquired schizencephaly.
DR   Orphanet; 93925; Alobar holoprosencephaly.
DR   Orphanet; 476119; Autosomal dominant preaxial polydactyly-upperback hypertrichosis syndrome.
DR   Orphanet; 98938; Colobomatous microphthalmia.
DR   Orphanet; 3332; Hypoplastic tibiae-postaxial polydactyly syndrome.
DR   Orphanet; 93924; Lobar holoprosencephaly.
DR   Orphanet; 280200; Microform holoprosencephaly.
DR   Orphanet; 93926; Midline interhemispheric variant of holoprosencephaly.
DR   Orphanet; 93336; Polydactyly of a triphalangeal thumb.
DR   Orphanet; 93321; Radial hemimelia.
DR   Orphanet; 220386; Semilobar holoprosencephaly.
DR   Orphanet; 280195; Septopreoptic holoprosencephaly.
DR   Orphanet; 93405; Syndactyly type 4.
DR   Orphanet; 2950; Triphalangeal thumb-polysyndactyly syndrome.
DR   PharmGKB; PA35752; -.
DR   VEuPathDB; HostDB:ENSG00000164690; -.
DR   eggNOG; KOG3638; Eukaryota.
DR   GeneTree; ENSGT00940000159119; -.
DR   HOGENOM; CLU_034686_0_0_1; -.
DR   InParanoid; Q15465; -.
DR   OMA; YTQSHEG; -.
DR   OrthoDB; 1169356at2759; -.
DR   PhylomeDB; Q15465; -.
DR   TreeFam; TF106458; -.
DR   PathwayCommons; Q15465; -.
DR   Reactome; R-HSA-373080; Class B/2 (Secretin family receptors).
DR   Reactome; R-HSA-5358346; Hedgehog ligand biogenesis.
DR   Reactome; R-HSA-5362768; Hh mutants are degraded by ERAD.
DR   Reactome; R-HSA-5362798; Release of Hh-Np from the secreting cell.
DR   Reactome; R-HSA-5632681; Ligand-receptor interactions.
DR   Reactome; R-HSA-5632684; Hedgehog 'on' state.
DR   Reactome; R-HSA-5635838; Activation of SMO.
DR   Reactome; R-HSA-5658034; HHAT G278V doesn't palmitoylate Hh-Np.
DR   SignaLink; Q15465; -.
DR   SIGNOR; Q15465; -.
DR   BioGRID-ORCS; 6469; 8 hits in 1015 CRISPR screens.
DR   ChiTaRS; SHH; human.
DR   EvolutionaryTrace; Q15465; -.
DR   GeneWiki; Sonic_hedgehog; -.
DR   GenomeRNAi; 6469; -.
DR   Pharos; Q15465; Tchem.
DR   PRO; PR:Q15465; -.
DR   Proteomes; UP000005640; Chromosome 7.
DR   RNAct; Q15465; protein.
DR   Bgee; ENSG00000164690; Expressed in left adrenal gland and 120 other tissues.
DR   ExpressionAtlas; Q15465; baseline and differential.
DR   Genevisible; Q15465; HS.
DR   GO; GO:0009986; C:cell surface; ISS:UniProtKB.
DR   GO; GO:0062023; C:collagen-containing extracellular matrix; HDA:BHF-UCL.
DR   GO; GO:0005829; C:cytosol; TAS:Reactome.
DR   GO; GO:0005788; C:endoplasmic reticulum lumen; TAS:Reactome.
DR   GO; GO:0005576; C:extracellular region; TAS:Reactome.
DR   GO; GO:0005615; C:extracellular space; IDA:UniProtKB.
DR   GO; GO:0045121; C:membrane raft; ISS:UniProtKB.
DR   GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR   GO; GO:0005509; F:calcium ion binding; IDA:UniProtKB.
DR   GO; GO:0004175; F:endopeptidase activity; TAS:Reactome.
DR   GO; GO:0005539; F:glycosaminoglycan binding; IEA:Ensembl.
DR   GO; GO:0043237; F:laminin-1 binding; ISS:UniProtKB.
DR   GO; GO:0016015; F:morphogen activity; TAS:ParkinsonsUK-UCL.
DR   GO; GO:0005113; F:patched binding; IDA:BHF-UCL.
DR   GO; GO:0008270; F:zinc ion binding; IDA:UniProtKB.
DR   GO; GO:0008209; P:androgen metabolic process; ISS:UniProtKB.
DR   GO; GO:0048645; P:animal organ formation; IEA:Ensembl.
DR   GO; GO:0097190; P:apoptotic signaling pathway; ISS:UniProtKB.
DR   GO; GO:0060840; P:artery development; IEA:Ensembl.
DR   GO; GO:0007411; P:axon guidance; ISS:UniProtKB.
DR   GO; GO:0060020; P:Bergmann glial cell differentiation; IEA:Ensembl.
DR   GO; GO:0007596; P:blood coagulation; IEA:Ensembl.
DR   GO; GO:0001569; P:branching involved in blood vessel morphogenesis; ISS:UniProtKB.
DR   GO; GO:0060445; P:branching involved in salivary gland morphogenesis; IEA:Ensembl.
DR   GO; GO:0001658; P:branching involved in ureteric bud morphogenesis; ISS:UniProtKB.
DR   GO; GO:0048754; P:branching morphogenesis of an epithelial tube; ISS:UniProtKB.
DR   GO; GO:0060447; P:bud outgrowth involved in lung branching; IEA:Ensembl.
DR   GO; GO:0043010; P:camera-type eye development; IEA:Ensembl.
DR   GO; GO:0060070; P:canonical Wnt signaling pathway; IEA:Ensembl.
DR   GO; GO:0043369; P:CD4-positive or CD8-positive, alpha-beta T cell lineage commitment; IDA:BHF-UCL.
DR   GO; GO:0048468; P:cell development; ISS:UniProtKB.
DR   GO; GO:0001708; P:cell fate specification; ISS:UniProtKB.
DR   GO; GO:0007267; P:cell-cell signaling; ISS:UniProtKB.
DR   GO; GO:0071285; P:cellular response to lithium ion; IEA:Ensembl.
DR   GO; GO:0007417; P:central nervous system development; ISS:UniProtKB.
DR   GO; GO:0021930; P:cerebellar granule cell precursor proliferation; ISS:UniProtKB.
DR   GO; GO:0003140; P:determination of left/right asymmetry in lateral mesoderm; ISS:BHF-UCL.
DR   GO; GO:0071542; P:dopaminergic neuron differentiation; TAS:ParkinsonsUK-UCL.
DR   GO; GO:0021904; P:dorsal/ventral neural tube patterning; IEA:Ensembl.
DR   GO; GO:0009953; P:dorsal/ventral pattern formation; ISS:UniProtKB.
DR   GO; GO:0007398; P:ectoderm development; IEA:Ensembl.
DR   GO; GO:0048557; P:embryonic digestive tract morphogenesis; IEA:Ensembl.
DR   GO; GO:0042733; P:embryonic digit morphogenesis; ISS:UniProtKB.
DR   GO; GO:0048617; P:embryonic foregut morphogenesis; IEA:Ensembl.
DR   GO; GO:0035115; P:embryonic forelimb morphogenesis; IEA:Ensembl.
DR   GO; GO:0035116; P:embryonic hindlimb morphogenesis; IEA:Ensembl.
DR   GO; GO:0030326; P:embryonic limb morphogenesis; ISS:UniProtKB.
DR   GO; GO:0009880; P:embryonic pattern specification; TAS:BHF-UCL.
DR   GO; GO:0048706; P:embryonic skeletal system development; IEA:Ensembl.
DR   GO; GO:0006897; P:endocytosis; IEA:Ensembl.
DR   GO; GO:0060664; P:epithelial cell proliferation involved in salivary gland morphogenesis; IEA:Ensembl.
DR   GO; GO:0060738; P:epithelial-mesenchymal signaling involved in prostate gland development; IDA:MGI.
DR   GO; GO:0030010; P:establishment of cell polarity; IEA:Ensembl.
DR   GO; GO:0030900; P:forebrain development; ISS:UniProtKB.
DR   GO; GO:0048859; P:formation of anatomical boundary; IEA:Ensembl.
DR   GO; GO:0031069; P:hair follicle morphogenesis; IEA:Ensembl.
DR   GO; GO:0007507; P:heart development; ISS:UniProtKB.
DR   GO; GO:0001947; P:heart looping; ISS:BHF-UCL.
DR   GO; GO:0030902; P:hindbrain development; ISS:UniProtKB.
DR   GO; GO:0007442; P:hindgut morphogenesis; IEA:Ensembl.
DR   GO; GO:0048839; P:inner ear development; IEA:Ensembl.
DR   GO; GO:0016539; P:intein-mediated protein splicing; IEA:InterPro.
DR   GO; GO:0045109; P:intermediate filament organization; IEA:Ensembl.
DR   GO; GO:0060459; P:left lung development; IEA:Ensembl.
DR   GO; GO:0060174; P:limb bud formation; IEA:Ensembl.
DR   GO; GO:0030324; P:lung development; ISS:UniProtKB.
DR   GO; GO:0060428; P:lung epithelium development; IEA:Ensembl.
DR   GO; GO:0060463; P:lung lobe morphogenesis; IEA:Ensembl.
DR   GO; GO:0060484; P:lung-associated mesenchyme development; IEA:Ensembl.
DR   GO; GO:0002320; P:lymphoid progenitor cell differentiation; IMP:BHF-UCL.
DR   GO; GO:0030539; P:male genitalia development; ISS:UniProtKB.
DR   GO; GO:0060916; P:mesenchymal cell proliferation involved in lung development; IEA:Ensembl.
DR   GO; GO:0060783; P:mesenchymal smoothened signaling pathway involved in prostate gland development; IEA:Ensembl.
DR   GO; GO:0072205; P:metanephric collecting duct development; IEP:UniProtKB.
DR   GO; GO:0072136; P:metanephric mesenchymal cell proliferation involved in metanephros development; ISS:UniProtKB.
DR   GO; GO:0001656; P:metanephros development; ISS:UniProtKB.
DR   GO; GO:0030901; P:midbrain development; ISS:UniProtKB.
DR   GO; GO:0045445; P:myoblast differentiation; IEA:Ensembl.
DR   GO; GO:0014902; P:myotube differentiation; IEA:Ensembl.
DR   GO; GO:0046639; P:negative regulation of alpha-beta T cell differentiation; IEA:Ensembl.
DR   GO; GO:0043066; P:negative regulation of apoptotic process; ISS:UniProtKB.
DR   GO; GO:0090090; P:negative regulation of canonical Wnt signaling pathway; IEA:Ensembl.
DR   GO; GO:0045596; P:negative regulation of cell differentiation; ISS:UniProtKB.
DR   GO; GO:0030336; P:negative regulation of cell migration; ISS:UniProtKB.
DR   GO; GO:0090370; P:negative regulation of cholesterol efflux; ISS:BHF-UCL.
DR   GO; GO:1904339; P:negative regulation of dopaminergic neuron differentiation; IEA:Ensembl.
DR   GO; GO:0010629; P:negative regulation of gene expression; IEA:Ensembl.
DR   GO; GO:2000357; P:negative regulation of kidney smooth muscle cell differentiation; ISS:UniProtKB.
DR   GO; GO:2001054; P:negative regulation of mesenchymal cell apoptotic process; IEA:Ensembl.
DR   GO; GO:0032435; P:negative regulation of proteasomal ubiquitin-dependent protein catabolic process; IEA:Ensembl.
DR   GO; GO:0042130; P:negative regulation of T cell proliferation; IEA:Ensembl.
DR   GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; ISS:BHF-UCL.
DR   GO; GO:0034244; P:negative regulation of transcription elongation from RNA polymerase II promoter; IEA:Ensembl.
DR   GO; GO:2000062; P:negative regulation of ureter smooth muscle cell differentiation; ISS:UniProtKB.
DR   GO; GO:0045060; P:negative thymic T cell selection; ISS:UniProtKB.
DR   GO; GO:0001755; P:neural crest cell migration; ISS:UniProtKB.
DR   GO; GO:0007405; P:neuroblast proliferation; ISS:UniProtKB.
DR   GO; GO:0048663; P:neuron fate commitment; ISS:UniProtKB.
DR   GO; GO:0042475; P:odontogenesis of dentin-containing tooth; IEA:Ensembl.
DR   GO; GO:0014003; P:oligodendrocyte development; IEA:Ensembl.
DR   GO; GO:0048709; P:oligodendrocyte differentiation; IBA:GO_Central.
DR   GO; GO:0002076; P:osteoblast development; IEA:Ensembl.
DR   GO; GO:0031016; P:pancreas development; IEA:Ensembl.
DR   GO; GO:0007389; P:pattern specification process; ISS:UniProtKB.
DR   GO; GO:0009949; P:polarity specification of anterior/posterior axis; ISS:UniProtKB.
DR   GO; GO:0046638; P:positive regulation of alpha-beta T cell differentiation; ISS:UniProtKB.
DR   GO; GO:0051781; P:positive regulation of cell division; IDA:BHF-UCL.
DR   GO; GO:0008284; P:positive regulation of cell population proliferation; IDA:BHF-UCL.
DR   GO; GO:0060769; P:positive regulation of epithelial cell proliferation involved in prostate gland development; IEA:Ensembl.
DR   GO; GO:0010628; P:positive regulation of gene expression; IEA:Ensembl.
DR   GO; GO:0007228; P:positive regulation of hh target transcription factor activity; ISS:BHF-UCL.
DR   GO; GO:0033092; P:positive regulation of immature T cell proliferation in thymus; ISS:BHF-UCL.
DR   GO; GO:2000358; P:positive regulation of kidney smooth muscle cell differentiation; ISS:UniProtKB.
DR   GO; GO:2000729; P:positive regulation of mesenchymal cell proliferation involved in ureter development; ISS:UniProtKB.
DR   GO; GO:0002052; P:positive regulation of neuroblast proliferation; IEA:Ensembl.
DR   GO; GO:0048714; P:positive regulation of oligodendrocyte differentiation; IEA:Ensembl.
DR   GO; GO:0042307; P:positive regulation of protein import into nucleus; IEA:Ensembl.
DR   GO; GO:0061189; P:positive regulation of sclerotome development; IDA:BHF-UCL.
DR   GO; GO:0014858; P:positive regulation of skeletal muscle cell proliferation; IEA:Ensembl.
DR   GO; GO:0048643; P:positive regulation of skeletal muscle tissue development; IEA:Ensembl.
DR   GO; GO:0045880; P:positive regulation of smoothened signaling pathway; IDA:UniProtKB.
DR   GO; GO:0051155; P:positive regulation of striated muscle cell differentiation; IEA:Ensembl.
DR   GO; GO:0033089; P:positive regulation of T cell differentiation in thymus; ISS:UniProtKB.
DR   GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; ISS:BHF-UCL.
DR   GO; GO:0045893; P:positive regulation of transcription, DNA-templated; IDA:BHF-UCL.
DR   GO; GO:2000063; P:positive regulation of ureter smooth muscle cell differentiation; ISS:UniProtKB.
DR   GO; GO:0030177; P:positive regulation of Wnt signaling pathway; IEA:Ensembl.
DR   GO; GO:0045059; P:positive thymic T cell selection; ISS:UniProtKB.
DR   GO; GO:0060516; P:primary prostatic bud elongation; IEA:Ensembl.
DR   GO; GO:0060523; P:prostate epithelial cord elongation; IEA:Ensembl.
DR   GO; GO:0030850; P:prostate gland development; ISS:UniProtKB.
DR   GO; GO:0016540; P:protein autoprocessing; IEA:InterPro.
DR   GO; GO:0034504; P:protein localization to nucleus; IEA:Ensembl.
DR   GO; GO:0042127; P:regulation of cell population proliferation; ISS:UniProtKB.
DR   GO; GO:0010468; P:regulation of gene expression; IBA:GO_Central.
DR   GO; GO:0060782; P:regulation of mesenchymal cell proliferation involved in prostate gland development; IEA:Ensembl.
DR   GO; GO:1900175; P:regulation of nodal signaling pathway involved in determination of lateral mesoderm left/right asymmetry; NAS:BHF-UCL.
DR   GO; GO:0042481; P:regulation of odontogenesis; ISS:BHF-UCL.
DR   GO; GO:0060685; P:regulation of prostatic bud formation; IEA:Ensembl.
DR   GO; GO:1900180; P:regulation of protein localization to nucleus; IDA:BHF-UCL.
DR   GO; GO:0030162; P:regulation of proteolysis; ISS:UniProtKB.
DR   GO; GO:0060458; P:right lung development; IEA:Ensembl.
DR   GO; GO:0060021; P:roof of mouth development; IEA:Ensembl.
DR   GO; GO:0060662; P:salivary gland cavitation; IEA:Ensembl.
DR   GO; GO:0048745; P:smooth muscle tissue development; IEP:UniProtKB.
DR   GO; GO:0007224; P:smoothened signaling pathway; IDA:FlyBase.
DR   GO; GO:0021938; P:smoothened signaling pathway involved in regulation of cerebellar granule cell precursor cell proliferation; IEA:Ensembl.
DR   GO; GO:0061053; P:somite development; ISS:BHF-UCL.
DR   GO; GO:0021513; P:spinal cord dorsal/ventral patterning; IEA:Ensembl.
DR   GO; GO:0021522; P:spinal cord motor neuron differentiation; IEA:Ensembl.
DR   GO; GO:0048864; P:stem cell development; ISS:UniProtKB.
DR   GO; GO:0014706; P:striated muscle tissue development; IEA:Ensembl.
DR   GO; GO:0033077; P:T cell differentiation in thymus; ISS:BHF-UCL.
DR   GO; GO:0021978; P:telencephalon regionalization; IEA:Ensembl.
DR   GO; GO:0021794; P:thalamus development; IEA:Ensembl.
DR   GO; GO:0048538; P:thymus development; ISS:UniProtKB.
DR   GO; GO:0030878; P:thyroid gland development; IEA:Ensembl.
DR   GO; GO:0060439; P:trachea morphogenesis; IEA:Ensembl.
DR   GO; GO:1905327; P:tracheoesophageal septum formation; IEA:Ensembl.
DR   GO; GO:0001570; P:vasculogenesis; ISS:UniProtKB.
DR   GO; GO:0007418; P:ventral midline development; TAS:BHF-UCL.
DR   Gene3D; 3.30.1380.10; -; 1.
DR   InterPro; IPR001657; Hedgehog.
DR   InterPro; IPR001767; Hedgehog_Hint.
DR   InterPro; IPR009045; Hedgehog_sig/DD-Pept_Zn-bd_sf.
DR   InterPro; IPR000320; Hedgehog_signalling_dom.
DR   InterPro; IPR003586; Hint_dom_C.
DR   InterPro; IPR003587; Hint_dom_N.
DR   InterPro; IPR036844; Hint_dom_sf.
DR   InterPro; IPR006141; Intein_N.
DR   Pfam; PF01085; HH_signal; 1.
DR   Pfam; PF01079; Hint; 1.
DR   PIRSF; PIRSF009400; Peptidase_C46; 1.
DR   PRINTS; PR00632; SONICHHOG.
DR   SMART; SM00305; HintC; 1.
DR   SMART; SM00306; HintN; 1.
DR   SUPFAM; SSF51294; SSF51294; 1.
DR   SUPFAM; SSF55166; SSF55166; 1.
DR   PROSITE; PS50817; INTEIN_N_TER; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Autocatalytic cleavage; Calcium; Cell membrane;
KW   Developmental protein; Direct protein sequencing; Disease variant;
KW   Endoplasmic reticulum; Glycoprotein; Golgi apparatus; Holoprosencephaly;
KW   Hydrolase; Lipoprotein; Membrane; Metal-binding; Microphthalmia; Palmitate;
KW   Protease; Reference proteome; Signal; Zinc.
FT   SIGNAL          1..23
FT                   /evidence="ECO:0000269|PubMed:9593755"
FT   CHAIN           24..462
FT                   /note="Sonic hedgehog protein"
FT                   /id="PRO_0000013208"
FT   CHAIN           24..197
FT                   /note="Sonic hedgehog protein N-product"
FT                   /id="PRO_0000013209"
FT   REGION          279..302
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          395..414
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   MOTIF           32..38
FT                   /note="Cardin-Weintraub"
FT                   /evidence="ECO:0000269|PubMed:23118222"
FT   METAL           89
FT                   /note="Calcium 1"
FT                   /evidence="ECO:0000269|PubMed:20504762,
FT                   ECO:0007744|PDB:3MXW"
FT   METAL           90
FT                   /note="Calcium 1"
FT                   /evidence="ECO:0000269|PubMed:20504762,
FT                   ECO:0007744|PDB:3MXW"
FT   METAL           90
FT                   /note="Calcium 2"
FT                   /evidence="ECO:0000269|PubMed:20504762,
FT                   ECO:0007744|PDB:3MXW"
FT   METAL           95
FT                   /note="Calcium 1"
FT                   /evidence="ECO:0000269|PubMed:20504762,
FT                   ECO:0007744|PDB:3MXW"
FT   METAL           125
FT                   /note="Calcium 1; via carbonyl oxygen"
FT                   /evidence="ECO:0000269|PubMed:20504762,
FT                   ECO:0007744|PDB:3MXW"
FT   METAL           126
FT                   /note="Calcium 1"
FT                   /evidence="ECO:0000269|PubMed:20504762,
FT                   ECO:0007744|PDB:3MXW"
FT   METAL           126
FT                   /note="Calcium 2"
FT                   /evidence="ECO:0000269|PubMed:20504762,
FT                   ECO:0007744|PDB:3MXW"
FT   METAL           129
FT                   /note="Calcium 2"
FT                   /evidence="ECO:0000269|PubMed:20504762,
FT                   ECO:0007744|PDB:3MXW"
FT   METAL           131
FT                   /note="Calcium 2"
FT                   /evidence="ECO:0000269|PubMed:20504762,
FT                   ECO:0007744|PDB:3MXW"
FT   METAL           140
FT                   /note="Zinc"
FT                   /evidence="ECO:0000269|PubMed:10753901,
FT                   ECO:0000269|PubMed:20504762, ECO:0007744|PDB:3M1N,
FT                   ECO:0007744|PDB:3MXW"
FT   METAL           147
FT                   /note="Zinc"
FT                   /evidence="ECO:0000269|PubMed:10753901,
FT                   ECO:0000269|PubMed:20504762, ECO:0007744|PDB:3M1N,
FT                   ECO:0007744|PDB:3MXW"
FT   METAL           182
FT                   /note="Zinc"
FT                   /evidence="ECO:0000269|PubMed:10753901,
FT                   ECO:0000269|PubMed:20504762, ECO:0007744|PDB:3M1N,
FT                   ECO:0007744|PDB:3MXW"
FT   SITE            197..198
FT                   /note="Cleavage; by autolysis"
FT                   /evidence="ECO:0000250"
FT   SITE            243
FT                   /note="Involved in cholesterol transfer"
FT                   /evidence="ECO:0000250"
FT   SITE            267
FT                   /note="Involved in auto-cleavage"
FT                   /evidence="ECO:0000250"
FT   SITE            270
FT                   /note="Essential for auto-cleavage"
FT                   /evidence="ECO:0000250"
FT   LIPID           24
FT                   /note="N-palmitoyl cysteine"
FT                   /evidence="ECO:0000269|PubMed:18534984,
FT                   ECO:0000269|PubMed:31875564, ECO:0000269|PubMed:9593755"
FT   LIPID           197
FT                   /note="Cholesterol glycine ester"
FT                   /evidence="ECO:0000250"
FT   CARBOHYD        278
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000269|PubMed:16335952"
FT   VARIANT         6
FT                   /note="R -> T (in HPE3)"
FT                   /evidence="ECO:0000269|PubMed:15221788,
FT                   ECO:0000269|PubMed:19603532"
FT                   /id="VAR_023804"
FT   VARIANT         17
FT                   /note="L -> P (in HPE3)"
FT                   /evidence="ECO:0000269|PubMed:19603532"
FT                   /id="VAR_062592"
FT   VARIANT         26
FT                   /note="P -> L (in HPE3)"
FT                   /evidence="ECO:0000269|PubMed:19603532"
FT                   /id="VAR_062593"
FT   VARIANT         27
FT                   /note="G -> A (in HPE3)"
FT                   /evidence="ECO:0000269|PubMed:15107988,
FT                   ECO:0000269|PubMed:19603532"
FT                   /id="VAR_039888"
FT   VARIANT         31
FT                   /note="G -> R (in HPE3; the same mutation in the mouse
FT                   sequence introduces a cleavage site for a furin-like
FT                   protease resulting in abnormal protein processing; cleavage
FT                   at this site removes 11 amino acids from the N-terminal
FT                   domain and reduces affinity of Shh for Ptch1 and signaling
FT                   potency in assays using chicken embryo neural plate
FT                   explants and mouse C3H10T1/2 stem cells; dbSNP:rs28936675)"
FT                   /evidence="ECO:0000269|PubMed:16282375,
FT                   ECO:0000269|PubMed:19603532, ECO:0000269|PubMed:8896572,
FT                   ECO:0000269|PubMed:9302262"
FT                   /id="VAR_003619"
FT   VARIANT         39
FT                   /note="L -> P (in HPE3; dbSNP:rs1428916820)"
FT                   /evidence="ECO:0000269|PubMed:19603532"
FT                   /id="VAR_062594"
FT   VARIANT         53
FT                   /note="E -> K (in HPE3)"
FT                   /evidence="ECO:0000269|PubMed:19603532"
FT                   /id="VAR_062595"
FT   VARIANT         83
FT                   /note="D -> V (in HPE3)"
FT                   /evidence="ECO:0000269|PubMed:19603532"
FT                   /id="VAR_062596"
FT   VARIANT         84
FT                   /note="I -> F (in HPE3)"
FT                   /evidence="ECO:0000269|PubMed:19603532"
FT                   /id="VAR_062597"
FT   VARIANT         88
FT                   /note="D -> V (in HPE3; familial; the same mutation in the
FT                   mouse sequence moderately reduces Ptch1 binding in vitro
FT                   and signaling potency in chicken embryo neural plate
FT                   explant assays compared with wild-type sequence;
FT                   dbSNP:rs104894050)"
FT                   /evidence="ECO:0000269|PubMed:10556296,
FT                   ECO:0000269|PubMed:16282375, ECO:0000269|PubMed:19603532"
FT                   /id="VAR_009163"
FT   VARIANT         100
FT                   /note="Q -> H (in HPE3; sporadic; in the mouse sequence
FT                   does not affect signaling activity in any of Shh signaling
FT                   assays and causes no apparent defects in cholesterol-
FT                   mediated autoprocessing reactions; dbSNP:rs587778792)"
FT                   /evidence="ECO:0000269|PubMed:10441331,
FT                   ECO:0000269|PubMed:15221788, ECO:0000269|PubMed:16282375,
FT                   ECO:0000269|PubMed:19603532"
FT                   /id="VAR_009164"
FT   VARIANT         102
FT                   /note="C -> R (in HPE3)"
FT                   /evidence="ECO:0000269|PubMed:19603532"
FT                   /id="VAR_062598"
FT   VARIANT         102
FT                   /note="C -> Y (in HPE3)"
FT                   /evidence="ECO:0000269|PubMed:19603532"
FT                   /id="VAR_062599"
FT   VARIANT         106..107
FT                   /note="Missing (in HPE3)"
FT                   /evidence="ECO:0000269|PubMed:15221788,
FT                   ECO:0000269|PubMed:19603532"
FT                   /id="VAR_023805"
FT   VARIANT         109
FT                   /note="L -> F (in HPE3)"
FT                   /evidence="ECO:0000269|PubMed:19603532"
FT                   /id="VAR_062600"
FT   VARIANT         110
FT                   /note="A -> D (in HPE3)"
FT                   /evidence="ECO:0000269|PubMed:15221788,
FT                   ECO:0000269|PubMed:19603532"
FT                   /id="VAR_023806"
FT   VARIANT         110
FT                   /note="A -> T (in HPE3)"
FT                   /evidence="ECO:0000269|PubMed:19603532"
FT                   /id="VAR_062601"
FT   VARIANT         111
FT                   /note="I -> F (in SMMCI; dbSNP:rs104894049)"
FT                   /evidence="ECO:0000269|PubMed:11471164,
FT                   ECO:0000269|PubMed:19603532"
FT                   /id="VAR_017883"
FT   VARIANT         111
FT                   /note="I -> N (in HPE3)"
FT                   /evidence="ECO:0000269|PubMed:15942952,
FT                   ECO:0000269|PubMed:19603532"
FT                   /id="VAR_039889"
FT   VARIANT         115
FT                   /note="N -> K (in HPE3; familial; in the mouse sequence
FT                   shows no change in activities at different temperatures;
FT                   dbSNP:rs267607047)"
FT                   /evidence="ECO:0000269|PubMed:10556296,
FT                   ECO:0000269|PubMed:16282375, ECO:0000269|PubMed:19603532"
FT                   /id="VAR_009165"
FT   VARIANT         117
FT                   /note="W -> G (in HPE3; the same mutation in the mouse
FT                   sequence causes a failure of Shh processing leading to
FT                   retention of the immature glycosylated protein within the
FT                   endoplasmic reticulum of transfected cells; causes a
FT                   temperature-dependent conformational change that allows Shh
FT                   to bind Ptch1 at 4 or 32 degrees Celsius but not at 37
FT                   degrees Celsius; the mutation drastically reduces signaling
FT                   potency in chicken embryo neural plate explant assays;
FT                   dbSNP:rs104894040)"
FT                   /evidence="ECO:0000269|PubMed:16282375,
FT                   ECO:0000269|PubMed:19603532, ECO:0000269|PubMed:8896572,
FT                   ECO:0000269|PubMed:9302262"
FT                   /id="VAR_003620"
FT   VARIANT         117
FT                   /note="W -> R (in HPE3; the same mutation in the mouse
FT                   sequence causes a failure of Shh processing leading to
FT                   retention of the immature glycosylated protein within the
FT                   endoplasmic reticulum of transfected cells; causes a
FT                   temperature-dependent conformational change that allows Shh
FT                   to bind Ptch1 at 4 or 32 degrees Celsius but not at 37
FT                   degrees Celsius; drastically reduces signaling potency in
FT                   chicken embryo neural plate explant assays;
FT                   dbSNP:rs104894040)"
FT                   /evidence="ECO:0000269|PubMed:16282375,
FT                   ECO:0000269|PubMed:19603532, ECO:0000269|PubMed:8896572,
FT                   ECO:0000269|PubMed:9302262"
FT                   /id="VAR_003621"
FT   VARIANT         124
FT                   /note="V -> M (in HPE3)"
FT                   /evidence="ECO:0000269|PubMed:19603532"
FT                   /id="VAR_062602"
FT   VARIANT         136
FT                   /note="E -> K (in HPE3)"
FT                   /evidence="ECO:0000269|PubMed:19603532"
FT                   /id="VAR_062603"
FT   VARIANT         140
FT                   /note="H -> P (in HPE3)"
FT                   /evidence="ECO:0000269|PubMed:11479728,
FT                   ECO:0000269|PubMed:19603532"
FT                   /id="VAR_039890"
FT   VARIANT         140
FT                   /note="H -> Q (in HPE3)"
FT                   /evidence="ECO:0000269|PubMed:15942953,
FT                   ECO:0000269|PubMed:17001669, ECO:0000269|PubMed:19603532"
FT                   /id="VAR_039891"
FT   VARIANT         143
FT                   /note="G -> D (in HPE3)"
FT                   /evidence="ECO:0000269|PubMed:19603532"
FT                   /id="VAR_062604"
FT   VARIANT         144
FT                   /note="R -> P (in HPE3)"
FT                   /evidence="ECO:0000269|PubMed:19603532"
FT                   /id="VAR_062605"
FT   VARIANT         147
FT                   /note="D -> N (in HPE3)"
FT                   /evidence="ECO:0000269|PubMed:19603532"
FT                   /id="VAR_062606"
FT   VARIANT         150
FT                   /note="T -> K (in HPE3)"
FT                   /evidence="ECO:0000269|PubMed:19603532"
FT                   /id="VAR_062607"
FT   VARIANT         150
FT                   /note="T -> R (in HPE3)"
FT                   /evidence="ECO:0000269|PubMed:15221788,
FT                   ECO:0000269|PubMed:19603532"
FT                   /id="VAR_023807"
FT   VARIANT         156
FT                   /note="S -> R (in HPE3; dbSNP:rs1554494372)"
FT                   /evidence="ECO:0000269|PubMed:19603532"
FT                   /id="VAR_062608"
FT   VARIANT         170
FT                   /note="F -> C (in HPE3)"
FT                   /evidence="ECO:0000269|PubMed:19603532"
FT                   /id="VAR_062609"
FT   VARIANT         171
FT                   /note="D -> H (in HPE3)"
FT                   /evidence="ECO:0000269|PubMed:19603532"
FT                   /id="VAR_062610"
FT   VARIANT         176..178
FT                   /note="Missing (in HPE3)"
FT                   /evidence="ECO:0000269|PubMed:15221788,
FT                   ECO:0000269|PubMed:19603532"
FT                   /id="VAR_023808"
FT   VARIANT         183
FT                   /note="C -> F (in HPE3)"
FT                   /evidence="ECO:0000269|PubMed:11479728,
FT                   ECO:0000269|PubMed:19603532"
FT                   /id="VAR_039892"
FT   VARIANT         183
FT                   /note="C -> R (in HPE3)"
FT                   /evidence="ECO:0000269|PubMed:19603532"
FT                   /id="VAR_062611"
FT   VARIANT         183
FT                   /note="C -> Y (in HPE3)"
FT                   /evidence="ECO:0000269|PubMed:19603532"
FT                   /id="VAR_062612"
FT   VARIANT         184
FT                   /note="S -> L (in HPE3)"
FT                   /evidence="ECO:0000269|PubMed:19603532"
FT                   /id="VAR_062613"
FT   VARIANT         188
FT                   /note="E -> Q (in HPE3; familial; dbSNP:rs587778799)"
FT                   /evidence="ECO:0000269|PubMed:10441331,
FT                   ECO:0000269|PubMed:15221788, ECO:0000269|PubMed:16282375,
FT                   ECO:0000269|PubMed:19603532"
FT                   /id="VAR_009166"
FT   VARIANT         196..200
FT                   /note="Missing (in HPE3)"
FT                   /evidence="ECO:0000269|PubMed:19603532"
FT                   /id="VAR_062614"
FT   VARIANT         196
FT                   /note="G -> E (in HPE3; dbSNP:rs752650571)"
FT                   /evidence="ECO:0000269|PubMed:19603532"
FT                   /id="VAR_062615"
FT   VARIANT         197
FT                   /note="G -> V (in HPE3)"
FT                   /evidence="ECO:0000269|PubMed:19603532"
FT                   /id="VAR_062616"
FT   VARIANT         198
FT                   /note="C -> F (in HPE3)"
FT                   /evidence="ECO:0000269|PubMed:19603532"
FT                   /id="VAR_062617"
FT   VARIANT         198
FT                   /note="C -> S (in HPE3)"
FT                   /evidence="ECO:0000269|PubMed:19603532"
FT                   /id="VAR_062618"
FT   VARIANT         218
FT                   /note="L -> P (in HPE3)"
FT                   /evidence="ECO:0000269|PubMed:17001669,
FT                   ECO:0000269|PubMed:19603532"
FT                   /id="VAR_062619"
FT   VARIANT         222
FT                   /note="D -> N (in HPE3; familial; dbSNP:rs587778805)"
FT                   /evidence="ECO:0000269|PubMed:10441331,
FT                   ECO:0000269|PubMed:15221788, ECO:0000269|PubMed:19603532"
FT                   /id="VAR_009167"
FT   VARIANT         224
FT                   /note="V -> E (in HPE3; dbSNP:rs104894042)"
FT                   /evidence="ECO:0000269|PubMed:19603532,
FT                   ECO:0000269|PubMed:9302262"
FT                   /id="VAR_009168"
FT   VARIANT         226
FT                   /note="A -> T (in HPE3; familial; dbSNP:rs104894043)"
FT                   /evidence="ECO:0000269|PubMed:19603532,
FT                   ECO:0000269|PubMed:9302262"
FT                   /id="VAR_009169"
FT   VARIANT         231
FT                   /note="G -> V (in HPE3)"
FT                   /evidence="ECO:0000269|PubMed:19603532"
FT                   /id="VAR_062620"
FT   VARIANT         232
FT                   /note="R -> G (in HPE3; dbSNP:rs1347054935)"
FT                   /evidence="ECO:0000269|PubMed:19603532"
FT                   /id="VAR_062621"
FT   VARIANT         234
FT                   /note="L -> P (in HPE3)"
FT                   /evidence="ECO:0000269|PubMed:19603532"
FT                   /id="VAR_062622"
FT   VARIANT         236
FT                   /note="S -> N (in HPE3)"
FT                   /evidence="ECO:0000269|PubMed:19603532"
FT                   /id="VAR_062623"
FT   VARIANT         236
FT                   /note="S -> R (in HPE3; familial; dbSNP:rs587778806)"
FT                   /evidence="ECO:0000269|PubMed:10556296,
FT                   ECO:0000269|PubMed:19603532"
FT                   /id="VAR_009170"
FT   VARIANT         241
FT                   /note="F -> L (in HPE3)"
FT                   /evidence="ECO:0000269|PubMed:19603532"
FT                   /id="VAR_062624"
FT   VARIANT         241
FT                   /note="F -> V (in HPE3)"
FT                   /evidence="ECO:0000269|PubMed:19603532"
FT                   /id="VAR_062625"
FT   VARIANT         255
FT                   /note="I -> N (in HPE3)"
FT                   /evidence="ECO:0000269|PubMed:19603532"
FT                   /id="VAR_062626"
FT   VARIANT         263..269
FT                   /note="Missing (in HPE3; sporadic)"
FT                   /evidence="ECO:0000269|PubMed:10556296,
FT                   ECO:0000269|PubMed:19603532"
FT                   /id="VAR_009171"
FT   VARIANT         267
FT                   /note="T -> I (in HPE3)"
FT                   /evidence="ECO:0000269|PubMed:15107988,
FT                   ECO:0000269|PubMed:19603532"
FT                   /id="VAR_039893"
FT   VARIANT         271
FT                   /note="L -> P (in HPE3)"
FT                   /evidence="ECO:0000269|PubMed:15221788,
FT                   ECO:0000269|PubMed:19603532"
FT                   /id="VAR_023809"
FT   VARIANT         275
FT                   /note="A -> E (in HPE3; dbSNP:rs556192490)"
FT                   /evidence="ECO:0000269|PubMed:19603532"
FT                   /id="VAR_062627"
FT   VARIANT         280
FT                   /note="S -> W (in HPE3)"
FT                   /evidence="ECO:0000269|PubMed:19603532"
FT                   /id="VAR_062628"
FT   VARIANT         290
FT                   /note="G -> D (in HPE3; sporadic; dbSNP:rs104894047)"
FT                   /evidence="ECO:0000269|PubMed:10556296,
FT                   ECO:0000269|PubMed:19603532"
FT                   /id="VAR_009172"
FT   VARIANT         296
FT                   /note="G -> A (in HPE3; unknown pathological significance;
FT                   dbSNP:rs955894039)"
FT                   /evidence="ECO:0000269|PubMed:19603532"
FT                   /id="VAR_062629"
FT   VARIANT         310
FT                   /note="R -> C (in HPE3)"
FT                   /evidence="ECO:0000269|PubMed:19603532"
FT                   /id="VAR_062630"
FT   VARIANT         321
FT                   /note="R -> S (in HPE3)"
FT                   /evidence="ECO:0000269|PubMed:19603532"
FT                   /id="VAR_062631"
FT   VARIANT         332
FT                   /note="V -> A (in HPE3 and SMMCI; dbSNP:rs104894052)"
FT                   /evidence="ECO:0000269|PubMed:15103725,
FT                   ECO:0000269|PubMed:15221788, ECO:0000269|PubMed:19603532"
FT                   /id="VAR_023810"
FT   VARIANT         346
FT                   /note="A -> V (in HPE3)"
FT                   /evidence="ECO:0000269|PubMed:19603532"
FT                   /id="VAR_062632"
FT   VARIANT         347
FT                   /note="P -> L (in HPE3; dbSNP:rs886042458)"
FT                   /evidence="ECO:0000269|PubMed:19603532"
FT                   /id="VAR_062633"
FT   VARIANT         347
FT                   /note="P -> Q (in HPE3)"
FT                   /evidence="ECO:0000269|PubMed:15221788,
FT                   ECO:0000269|PubMed:19603532"
FT                   /id="VAR_023811"
FT   VARIANT         347
FT                   /note="P -> R (in HPE3; dbSNP:rs886042458)"
FT                   /evidence="ECO:0000269|PubMed:19603532"
FT                   /id="VAR_062634"
FT   VARIANT         354
FT                   /note="I -> T (in HPE3)"
FT                   /evidence="ECO:0000269|PubMed:15221788,
FT                   ECO:0000269|PubMed:19603532"
FT                   /id="VAR_023812"
FT   VARIANT         362
FT                   /note="S -> L (in HPE3)"
FT                   /evidence="ECO:0000269|PubMed:19603532"
FT                   /id="VAR_062635"
FT   VARIANT         363
FT                   /note="C -> Y (in HPE3)"
FT                   /evidence="ECO:0000269|PubMed:17001669,
FT                   ECO:0000269|PubMed:19603532"
FT                   /id="VAR_062636"
FT   VARIANT         364
FT                   /note="Y -> C (in HPE3)"
FT                   /evidence="ECO:0000269|PubMed:19603532"
FT                   /id="VAR_062637"
FT   VARIANT         373
FT                   /note="A -> T (in HPE3)"
FT                   /evidence="ECO:0000269|PubMed:15107988,
FT                   ECO:0000269|PubMed:19603532"
FT                   /id="VAR_039894"
FT   VARIANT         374
FT                   /note="H -> R (in HPE3)"
FT                   /evidence="ECO:0000269|PubMed:19603532"
FT                   /id="VAR_062638"
FT   VARIANT         376
FT                   /note="A -> D (in HPE3)"
FT                   /evidence="ECO:0000269|PubMed:19603532"
FT                   /id="VAR_062639"
FT   VARIANT         377
FT                   /note="F -> S (in HPE3)"
FT                   /evidence="ECO:0000269|PubMed:19603532"
FT                   /id="VAR_062640"
FT   VARIANT         378..380
FT                   /note="Missing (in HPE3; familial)"
FT                   /evidence="ECO:0000269|PubMed:19603532"
FT                   /id="VAR_009173"
FT   VARIANT         381
FT                   /note="R -> P (in HPE3)"
FT                   /evidence="ECO:0000269|PubMed:15221788,
FT                   ECO:0000269|PubMed:19603532"
FT                   /id="VAR_023813"
FT   VARIANT         382
FT                   /note="L -> P (in HPE3)"
FT                   /evidence="ECO:0000269|PubMed:19603532"
FT                   /id="VAR_062641"
FT   VARIANT         383
FT                   /note="A -> T (in HPE3; sporadic; dbSNP:rs137853341)"
FT                   /evidence="ECO:0000269|PubMed:19603532,
FT                   ECO:0000269|PubMed:9302262"
FT                   /id="VAR_009174"
FT   VARIANT         391
FT                   /note="A -> T (in HPE3; unknown pathological significance;
FT                   dbSNP:rs1131692264)"
FT                   /evidence="ECO:0000269|PubMed:19603532"
FT                   /id="VAR_062642"
FT   VARIANT         401..408
FT                   /note="Missing (in ocular coloboma)"
FT                   /evidence="ECO:0000269|PubMed:12503095"
FT                   /id="VAR_017884"
FT   VARIANT         402..409
FT                   /note="Missing (in HPE3; unknown pathological
FT                   significance)"
FT                   /evidence="ECO:0000269|PubMed:19603532"
FT                   /id="VAR_062643"
FT   VARIANT         404..408
FT                   /note="Missing (in HPE3; familial)"
FT                   /id="VAR_009175"
FT   VARIANT         405..409
FT                   /note="Missing (in HPE3; unknown pathological
FT                   significance)"
FT                   /evidence="ECO:0000269|PubMed:19603532"
FT                   /id="VAR_062644"
FT   VARIANT         411
FT                   /note="G -> GG (in HPE3; unknown pathological
FT                   significance)"
FT                   /evidence="ECO:0000269|PubMed:19603532"
FT                   /id="VAR_062645"
FT   VARIANT         416
FT                   /note="T -> A (in HPE3; unknown pathological significance;
FT                   dbSNP:rs1412744230)"
FT                   /evidence="ECO:0000269|PubMed:19603532"
FT                   /id="VAR_062646"
FT   VARIANT         424
FT                   /note="P -> A (in HPE3; familial; dbSNP:rs104894048)"
FT                   /evidence="ECO:0000269|PubMed:10556296,
FT                   ECO:0000269|PubMed:19603532"
FT                   /id="VAR_009176"
FT   VARIANT         435
FT                   /note="Y -> N (in HPE3)"
FT                   /evidence="ECO:0000269|PubMed:19603532"
FT                   /id="VAR_062647"
FT   VARIANT         436
FT                   /note="S -> L (in HPE3; sporadic)"
FT                   /evidence="ECO:0000269|PubMed:10556296,
FT                   ECO:0000269|PubMed:19603532"
FT                   /id="VAR_009177"
FT   VARIANT         456
FT                   /note="G -> R (in HPE3; unknown pathological significance)"
FT                   /evidence="ECO:0000269|PubMed:19603532"
FT                   /id="VAR_062648"
FT   MUTAGEN         24
FT                   /note="C->S,A: Abolishes palmitoylation."
FT                   /evidence="ECO:0000269|PubMed:18534984,
FT                   ECO:0000269|PubMed:31875564, ECO:0000269|PubMed:9593755"
FT   STRAND          30..32
FT                   /evidence="ECO:0007829|PDB:3M1N"
FT   STRAND          47..51
FT                   /evidence="ECO:0007829|PDB:6PJV"
FT   TURN            56..59
FT                   /evidence="ECO:0007829|PDB:6PJV"
FT   HELIX           71..74
FT                   /evidence="ECO:0007829|PDB:6PJV"
FT   STRAND          84..86
FT                   /evidence="ECO:0007829|PDB:6PJV"
FT   STRAND          91..93
FT                   /evidence="ECO:0007829|PDB:3MXW"
FT   HELIX           94..96
FT                   /evidence="ECO:0007829|PDB:6PJV"
FT   HELIX           100..116
FT                   /evidence="ECO:0007829|PDB:6PJV"
FT   STRAND          122..126
FT                   /evidence="ECO:0007829|PDB:6PJV"
FT   HELIX           139..141
FT                   /evidence="ECO:0007829|PDB:6PJV"
FT   STRAND          145..150
FT                   /evidence="ECO:0007829|PDB:6PJV"
FT   HELIX           155..157
FT                   /evidence="ECO:0007829|PDB:6PJV"
FT   HELIX           158..167
FT                   /evidence="ECO:0007829|PDB:6PJV"
FT   STRAND          171..177
FT                   /evidence="ECO:0007829|PDB:6PJV"
FT   STRAND          180..184
FT                   /evidence="ECO:0007829|PDB:6PJV"
FT   HELIX           188..190
FT                   /evidence="ECO:0007829|PDB:3MXW"
SQ   SEQUENCE   462 AA;  49607 MW;  DD687AFA582A4749 CRC64;
     MLLLARCLLL VLVSSLLVCS GLACGPGRGF GKRRHPKKLT PLAYKQFIPN VAEKTLGASG
     RYEGKISRNS ERFKELTPNY NPDIIFKDEE NTGADRLMTQ RCKDKLNALA ISVMNQWPGV
     KLRVTEGWDE DGHHSEESLH YEGRAVDITT SDRDRSKYGM LARLAVEAGF DWVYYESKAH
     IHCSVKAENS VAAKSGGCFP GSATVHLEQG GTKLVKDLSP GDRVLAADDQ GRLLYSDFLT
     FLDRDDGAKK VFYVIETREP RERLLLTAAH LLFVAPHNDS ATGEPEASSG SGPPSGGALG
     PRALFASRVR PGQRVYVVAE RDGDRRLLPA AVHSVTLSEE AAGAYAPLTA QGTILINRVL
     ASCYAVIEEH SWAHRAFAPF RLAHALLAAL APARTDRGGD SGGGDRGGGG GRVALTAPGA
     ADAPGAGATA GIHWYSQLLY QIGTWLLDSE ALHPLGMAVK SS
//
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