ID HNF1A_HUMAN Reviewed; 631 AA.
AC P20823; A5Z2R8; Q2M3H2; Q99861;
DT 01-FEB-1991, integrated into UniProtKB/Swiss-Prot.
DT 16-AUG-2004, sequence version 2.
DT 29-MAY-2013, entry version 168.
DE RecName: Full=Hepatocyte nuclear factor 1-alpha;
DE Short=HNF-1-alpha;
DE Short=HNF-1A;
DE AltName: Full=Liver-specific transcription factor LF-B1;
DE Short=LFB1;
DE AltName: Full=Transcription factor 1;
DE Short=TCF-1;
GN Name=HNF1A; Synonyms=TCF1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Liver;
RX PubMed=1707031; DOI=10.1016/0888-7543(90)90238-P;
RA Bach I., Galcheva-Gargova Z., Mattei M.-G., Simon-Chazottes D.,
RA Guenet J.-L., Cereghini S., Yaniv M.;
RT "Cloning of human hepatic nuclear factor 1 (HNF1) and chromosomal
RT localization of its gene in man and mouse.";
RL Genomics 8:155-164(1990).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Liver;
RX PubMed=7900999;
RA Bach I., Yaniv M.;
RT "More potent transcriptional activators or a transdominant inhibitor
RT of the HNF1 homeoprotein family are generated by alternative RNA
RT processing.";
RL EMBO J. 12:4229-4242(1993).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT MODY3 LEU-447.
RX PubMed=8945470; DOI=10.1038/384455a0;
RA Yamagata K., Oda N., Kaisaki P.J., Menzel S., Furuta H.,
RA Vaxillaire M., Southam L., Cox R.D., Lathrop G.M., Boriraj V.V.,
RA Chen X., Cox N.J., Oda Y., Yano H., le Beau M.M., Yamada S.,
RA Nishigori H., Takeda J., Fajans S.S., Hattersley A.T., Iwasaki N.,
RA Hansen T., Pedersen O., Polonsky K.S., Turner R.C., Velho G.,
RA Chevre J.-C., Froguel P., Bell G.I.;
RT "Mutations in the hepatocyte nuclear factor-1alpha gene in maturity-
RT onset diabetes of the young (MODY3).";
RL Nature 384:455-458(1996).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS LEU-27; VAL-98;
RP ASN-487 AND SER-574.
RG SeattleSNPs variation discovery resource;
RL Submitted (MAY-2007) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16541075; DOI=10.1038/nature04569;
RA Scherer S.E., Muzny D.M., Buhay C.J., Chen R., Cree A., Ding Y.,
RA Dugan-Rocha S., Gill R., Gunaratne P., Harris R.A., Hawes A.C.,
RA Hernandez J., Hodgson A.V., Hume J., Jackson A., Khan Z.M.,
RA Kovar-Smith C., Lewis L.R., Lozado R.J., Metzker M.L.,
RA Milosavljevic A., Miner G.R., Montgomery K.T., Morgan M.B.,
RA Nazareth L.V., Scott G., Sodergren E., Song X.-Z., Steffen D.,
RA Lovering R.C., Wheeler D.A., Worley K.C., Yuan Y., Zhang Z.,
RA Adams C.Q., Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., Chen Z.,
RA Clerc-Blankenburg K.P., Davis C., Delgado O., Dinh H.H., Draper H.,
RA Gonzalez-Garay M.L., Havlak P., Jackson L.R., Jacob L.S., Kelly S.H.,
RA Li L., Li Z., Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V.,
RA Okwuonu G.O., Pasternak S., Perez L.M., Plopper F.J.H., Santibanez J.,
RA Shen H., Tabor P.E., Verduzco D., Waldron L., Wang Q., Williams G.A.,
RA Zhang J., Zhou J., Allen C.C., Amin A.G., Anyalebechi V., Bailey M.,
RA Barbaria J.A., Bimage K.E., Bryant N.P., Burch P.E., Burkett C.E.,
RA Burrell K.L., Calderon E., Cardenas V., Carter K., Casias K.,
RA Cavazos I., Cavazos S.R., Ceasar H., Chacko J., Chan S.N., Chavez D.,
RA Christopoulos C., Chu J., Cockrell R., Cox C.D., Dang M.,
RA Dathorne S.R., David R., Davis C.M., Davy-Carroll L., Deshazo D.R.,
RA Donlin J.E., D'Souza L., Eaves K.A., Egan A., Emery-Cohen A.J.,
RA Escotto M., Flagg N., Forbes L.D., Gabisi A.M., Garza M., Hamilton C.,
RA Henderson N., Hernandez O., Hines S., Hogues M.E., Huang M.,
RA Idlebird D.G., Johnson R., Jolivet A., Jones S., Kagan R., King L.M.,
RA Leal B., Lebow H., Lee S., LeVan J.M., Lewis L.C., London P.,
RA Lorensuhewa L.M., Loulseged H., Lovett D.A., Lucier A., Lucier R.L.,
RA Ma J., Madu R.C., Mapua P., Martindale A.D., Martinez E., Massey E.,
RA Mawhiney S., Meador M.G., Mendez S., Mercado C., Mercado I.C.,
RA Merritt C.E., Miner Z.L., Minja E., Mitchell T., Mohabbat F.,
RA Mohabbat K., Montgomery B., Moore N., Morris S., Munidasa M.,
RA Ngo R.N., Nguyen N.B., Nickerson E., Nwaokelemeh O.O., Nwokenkwo S.,
RA Obregon M., Oguh M., Oragunye N., Oviedo R.J., Parish B.J.,
RA Parker D.N., Parrish J., Parks K.L., Paul H.A., Payton B.A., Perez A.,
RA Perrin W., Pickens A., Primus E.L., Pu L.-L., Puazo M., Quiles M.M.,
RA Quiroz J.B., Rabata D., Reeves K., Ruiz S.J., Shao H., Sisson I.,
RA Sonaike T., Sorelle R.P., Sutton A.E., Svatek A.F., Svetz L.A.,
RA Tamerisa K.S., Taylor T.R., Teague B., Thomas N., Thorn R.D.,
RA Trejos Z.Y., Trevino B.K., Ukegbu O.N., Urban J.B., Vasquez L.I.,
RA Vera V.A., Villasana D.M., Wang L., Ward-Moore S., Warren J.T.,
RA Wei X., White F., Williamson A.L., Wleczyk R., Wooden H.S.,
RA Wooden S.H., Yen J., Yoon L., Yoon V., Zorrilla S.E., Nelson D.,
RA Kucherlapati R., Weinstock G., Gibbs R.A.;
RT "The finished DNA sequence of human chromosome 12.";
RL Nature 440:346-351(2006).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT LEU-27.
RC TISSUE=Liver;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [8]
RP X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 85-278 IN COMPLEX WITH DNA,
RP FUNCTION, DNA-BINDING, MUTAGENESIS OF ASN-127; GLU-132; PHE-177;
RP ILE-186; THR-190; ASN-202; VAL-246 AND ASN-257, AND CHARACTERIZATION
RP OF VARIANTS MODY3 PHE-142 AND GLN-205.
RX PubMed=12453420; DOI=10.1016/S1097-2765(02)00704-9;
RA Chi Y.I., Frantz J.D., Oh B.C., Hansen L., Dhe-Paganon S.,
RA Shoelson S.E.;
RT "Diabetes mutations delineate an atypical POU domain in HNF-1alpha.";
RL Mol. Cell 10:1129-1137(2002).
RN [9]
RP X-RAY CRYSTALLOGRAPHY (1.4 ANGSTROMS) OF 2-32, AND CIRCULAR DICHROISM.
RX PubMed=16930618; DOI=10.1016/j.jmb.2006.06.086;
RA Narayana N., Phillips N.B., Hua Q.X., Jia W., Weiss M.A.;
RT "Diabetes mellitus due to misfolding of a beta-cell transcription
RT factor: stereospecific frustration of a Schellman motif in HNF-
RT 1alpha.";
RL J. Mol. Biol. 362:414-429(2006).
RN [10]
RP VARIANTS MODY3 ARG-107; TRP-131; MET-260 AND HIS-272.
RX PubMed=9166684;
RA Glucksmann M.A., Lehto M., Tayber O., Scotti S., Berkemeier L.,
RA Pulido J.C., Wu Y., Nir W.-J., Fang L., Markel P., Munnelly K.D.,
RA Goranson J., Orho M., Young B.M., Whitacre J.L., McMenimen C.,
RA Wantman M., Tuomi T., Warram J., Forsblom C.M., Carlsson M.,
RA Rosenzweig J., Kennedy G., Duyk G.M., Krolewski A.S., Groop L.C.,
RA Thomas J.D.;
RT "Novel mutations and a mutational hotspot in the MODY3 gene.";
RL Diabetes 46:1081-1086(1997).
RN [11]
RP VARIANTS MODY3 HIS-12; GLN-131; GLN-205 AND CYS-263, AND VARIANT NIDDM
RP ASP-191.
RX PubMed=9287053;
RA Iwasaki N., Oda N., Ogata M., Hara M., Hinokio Y., Oda Y.,
RA Yamagata K., Kanematsu S., Ohgawara H., Omori Y., Bell G.I.;
RT "Mutations in the hepatocyte nuclear factor-1alpha/MODY3 gene in
RT Japanese subjects with early- and late-onset NIDDM.";
RL Diabetes 46:1504-1508(1997).
RN [12]
RP VARIANT NIDDM MET-254, AND VARIANTS LEU-27 AND ASN-487.
RX PubMed=9287055;
RA Yamada S., Nishigori H., Onda H., Takahashi K., Kitano N.,
RA Morikawa A., Takeuchi T., Takeda J.;
RT "Mutations in the hepatocyte nuclear factor-1alpha gene (MODY3) are
RT not a major cause of late-onset NIDDM in Japanese subjects.";
RL Diabetes 46:1512-1513(1997).
RN [13]
RP VARIANTS IDDM20 HIS-272 AND GLY-583.
RX PubMed=9313763;
RA Yamada S., Nishigori H., Onda H., Utsugi T., Yanagawa T., Maruyama T.,
RA Onigata K., Nagashima K., Nagai R., Morikawa A., Takeuchi T.,
RA Takeda J.;
RT "Identification of mutations in the hepatocyte nuclear factor (HNF)-1-
RT alpha gene in Japanese subjects with IDDM.";
RL Diabetes 46:1643-1647(1997).
RN [14]
RP VARIANTS MODY3, AND VARIANT ATYPICAL DIABETES SER-574.
RX PubMed=9392505;
RA Boutin P., Chevre J.-C., Hani E.H., Gomis R., Pardini V.C.,
RA Guillausseau P.-J., Vaxillaire M., Velho G., Froguel P.;
RT "An automated fluorescent single-strand conformation polymorphism
RT technique for screening mutations in the hepatocyte nuclear factor-
RT 1alpha gene (maturity-onset diabetes of the young).";
RL Diabetes 46:2108-2109(1997).
RN [15]
RP VARIANTS MODY3 GLN-131; GLN-229; GLY-241 AND HIS-272.
RX PubMed=9032114;
RA Kaisaki P.J., Menzel S., Lindner T., Oda N., Rjasanowski I., Sahm J.,
RA Meincke G., Schulze J., Schmechel H., Petzold C., Ledermann H.M.,
RA Sachse G., Boriraj V.V., Menzel R., Kerner W., Turner R.C.,
RA Yamagata K., Bell G.I.;
RT "Mutations in the hepatocyte nuclear factor-1alpha gene in MODY and
RT early-onset NIDDM: evidence for a mutational hotspot in exon 4.";
RL Diabetes 46:528-535(1997).
RN [16]
RP VARIANTS MODY3 THR-129; TRP-131; TRP-159; LEU-519 AND ILE-620.
RX PubMed=9075818;
RA Frayling T.M., Bulman M.P., Ellard S., Appleton M., Dronsfield M.J.,
RA Mackie A.D., Baird J.D., Kaisaki P.J., Yamagata K., Bell G.I.,
RA Bain S.C., Hattersley A.T.;
RT "Mutations in the hepatocyte nuclear factor-1alpha gene are a common
RT cause of maturity-onset diabetes of the young in the U.K.";
RL Diabetes 46:720-725(1997).
RN [17]
RP VARIANTS MODY3 ASN-128; TYR-143 AND LEU-447.
RX PubMed=9075819;
RA Hansen T., Eiberg H., Rouard M., Vaxillaire M., Moeller A.M.,
RA Rasmussen S.K., Fridberg M., Urhammer S.A., Holst J.J., Almind K.,
RA Echwald S.M., Hansen L., Bell G.I., Pedersen O.;
RT "Novel MODY3 mutations in the hepatocyte nuclear factor-1alpha gene:
RT evidence for a hyperexcitability of pancreatic beta-cells to
RT intravenous secretagogues in a glucose-tolerant carrier of a P447L
RT mutation.";
RL Diabetes 46:726-730(1997).
RN [18]
RP VARIANTS LEU-27; VAL-98 AND ASN-487.
RX PubMed=9133564;
RA Urhammer S.A., Fridberg M., Hansen T., Rasmussen S.K., Moeller A.M.,
RA Clausen J.O., Pedersen O.;
RT "A prevalent amino acid polymorphism at codon 98 in the hepatocyte
RT nuclear factor-1alpha gene is associated with reduced serum C-peptide
RT and insulin responses to an oral glucose challenge.";
RL Diabetes 46:912-916(1997).
RN [19]
RP VARIANT NIDDM GLN-583, AND VARIANTS LEU-27; VAL-98 AND ASN-487.
RX PubMed=9112026; DOI=10.1007/s001250050703;
RA Urhammer S.A., Rasmussen S.K., Kaisaki P.J., Oda N., Yamagata K.,
RA Moeller A.M., Fridberg M., Hansen L., Hansen T., Bell G.I.,
RA Pedersen O.;
RT "Genetic variation in the hepatocyte nuclear factor-1 alpha gene in
RT Danish Caucasians with late-onset NIDDM.";
RL Diabetologia 40:473-475(1997).
RN [20]
RP VARIANTS MODY3 CYS-122; PHE-142 AND GLN-159.
RX PubMed=9097962; DOI=10.1093/hmg/6.4.583;
RA Vaxillaire M., Rouard M., Yamagata K., Oda N., Kaisaki P.J.,
RA Boriraj V.V., Chevre J.-C., Boccio V., Cox R.D., Lathrop G.M.,
RA Dussoix P., Philippe J., Timsit J., Charpentier G., Velho G.,
RA Bell G.I., Froguel P.;
RT "Identification of nine novel mutations in the hepatocyte nuclear
RT factor 1 alpha gene associated with maturity-onset diabetes of the
RT young (MODY3).";
RL Hum. Mol. Genet. 6:583-586(1997).
RN [21]
RP VARIANTS LEU-27; ASN-487 AND ARG-514.
RX PubMed=9604876;
RA Behn P.S., Wasson J., Chayen S., Smolovitch I., Thomas J.D.,
RA Glaser B., Permutt M.A.;
RT "Hepatocyte nuclear factor 1alpha coding mutations are an uncommon
RT contributor to early-onset type 2 diabetes in Ashkenazi Jews.";
RL Diabetes 47:967-969(1998).
RN [22]
RP VARIANTS MODY3 ASP-31; TRP-159; THR-161; TRP-200 AND TRP-271.
RX PubMed=9754819; DOI=10.1007/s001250051025;
RA Chevre J.-C., Hani E.H., Boutin P., Vaxillaire M., Blanche H.,
RA Vionnet N., Pardini V.C., Timsit J., Larger E., Charpentier G.,
RA Beckers D., Maes M., Bellanne-Chantelot C., Velho G., Froguel P.;
RT "Mutation screening in 18 Caucasian families suggest the existence of
RT other MODY genes.";
RL Diabetologia 41:1017-1023(1998).
RN [23]
RP VARIANTS IDDM20 LYS-48 AND GLY-241.
RX PubMed=9867222; DOI=10.1007/s001250051101;
RA Moeller A.M., Dalgaard L.T., Pociot F., Nerup J., Hansen T.,
RA Pedersen O.;
RT "Mutations in the hepatocyte nuclear factor-1alpha gene in Caucasian
RT families originally classified as having type I diabetes.";
RL Diabetologia 41:1528-1531(1998).
RN [24]
RP VARIANTS MODY3 ARG-537 AND LYS-619.
RX PubMed=9626139; DOI=10.1210/jc.83.6.2059;
RA Elbein S.C., Teng K., Yount P., Scroggin E.;
RT "Linkage and molecular scanning analyses of MODY3/hepatocyte nuclear
RT factor-1 alpha gene in typical familial type 2 diabetes: evidence for
RT novel mutations in exons 8 and 10.";
RL J. Clin. Endocrinol. Metab. 83:2059-2065(1998).
RN [25]
RP VARIANTS LEU-27 AND ASN-487.
RX PubMed=9621514; DOI=10.1007/s100380050049;
RA Nishigori H., Yamada S., Kohama T., Utsugi T., Shimizu H.,
RA Takeuchi T., Takeda J.;
RT "Mutations in the hepatocyte nuclear factor-1 alpha gene 'MODY3' are
RT not a major cause of early-onset non-insulin-dependent 'type 2'
RT diabetes mellitus in Japanese.";
RL J. Hum. Genet. 43:107-110(1998).
RN [26]
RP VARIANTS MODY3 HIS-12; ASN-158; GLN-159 AND CYS-203.
RX PubMed=10078571;
RA Yamada S., Tomura H., Nishigori H., Sho K., Mabe H., Iwatani N.,
RA Takumi T., Kito Y., Moriya N., Muroya K., Ogata T., Onigata K.,
RA Morikawa A., Inoue I., Takeda J.;
RT "Identification of mutations in the hepatocyte nuclear factor-1alpha
RT gene in Japanese subjects with early-onset NIDDM and functional
RT analysis of the mutant proteins.";
RL Diabetes 48:645-648(1999).
RN [27]
RP VARIANTS MODY3 GLU-117 AND TYR-143.
RX PubMed=10102714;
RA Ellard S., Bulman M.P., Frayling T.M., Allen L.I.S., Dronsfield M.J.,
RA Tack C.J., Hattersley A.T.;
RT "Allelic drop-out in exon 2 of the hepatocyte nuclear factor-1alpha
RT gene hinders the identification of mutations in three families with
RT maturity-onset diabetes of the young.";
RL Diabetes 48:921-923(1999).
RN [28]
RP VARIANT NIDDM CYS-272, AND VARIANT IDDM20 ARG-415.
RX PubMed=10333057; DOI=10.1007/s001250051204;
RA Yoshiuchi I., Yamagata K., Yang Q., Iwahashi H., Okita K.,
RA Yamamoto K., Oue T., Imagawa A., Hamaguchi T., Yamasaki T.,
RA Horikawa Y., Satoh T., Nakajima H., Miyazaki J., Higashiyama S.,
RA Miyagawa J., Namba M., Hanafusa T., Matsuzawa Y.;
RT "Three new mutations in the hepatocyte nuclear factor-1alpha gene in
RT Japanese subjects with diabetes mellitus: clinical features and
RT functional characterization.";
RL Diabetologia 42:621-626(1999).
RN [29]
RP VARIANTS MODY3 ARG-20; HIS-203; CYS-432 AND MET-618.
RX PubMed=10588527; DOI=10.1046/j.1464-5491.1999.00188.x;
RA Ng M.C.Y., Cockburn B.N., Lindner T.H., Yeung V.T.F., Chow C.-C.,
RA So W.-Y., Li J.K.Y., Lo Y.M.D., Lee Z.S.K., Cockram C.S.,
RA Critchley J.A.J.H., Bell G.I., Chan J.C.N.;
RT "Molecular genetics of diabetes mellitus in Chinese subjects:
RT identification of mutations in glucokinase and hepatocyte nuclear
RT factor-1alpha genes in patients with early-onset type 2 diabetes
RT mellitus/MODY.";
RL Diabet. Med. 16:956-963(1999).
RN [30]
RP VARIANT MODY3 ILE-620.
RX PubMed=10482964; DOI=10.1038/sj.ejhg.5200358;
RA Miedzybrodzka Z., Hattersley A.T., Ellard S., Pearson D., de Silva D.,
RA Harvey R., Haites N.;
RT "Non-penetrance in a MODY 3 family with a mutation in the hepatic
RT nuclear factor 1alpha gene: implications for predictive testing.";
RL Eur. J. Hum. Genet. 7:729-732(1999).
RN [31]
RP VARIANT SER-319.
RX PubMed=10084598; DOI=10.1210/jc.84.3.1077;
RA Hegele R.A., Cao H., Harris S.B., Hanley A.J.G., Zinman B.;
RT "The hepatic nuclear factor-1alpha G319S variant is associated with
RT early-onset type 2 diabetes in Canadian Oji-Cree.";
RL J. Clin. Endocrinol. Metab. 84:1077-1082(1999).
RN [32]
RP CHARACTERIZATION OF VARIANTS MODY3 HIS-12; ARG-20 AND ASP-31,
RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH PCBD1.
RX PubMed=10966642; DOI=10.1038/78966;
RA Rose R.B., Bayle J.H., Endrizzi J.A., Cronk J.D., Crabtree G.R.,
RA Alber T.;
RT "Structural basis of dimerization, coactivator recognition and MODY3
RT mutations in HNF-1alpha.";
RL Nat. Struct. Biol. 7:744-748(2000).
RN [33]
RP INVOLVEMENT IN HEPATIC ADENOMAS, AND VARIANTS TYR-127; CYS-165;
RP CYS-206; LEU-206; SER-237; GLY-244; PRO-250; CYS-268; GLU-273; SER-574
RP AND GLN-583.
RX PubMed=12355088; DOI=10.1038/ng1001;
RA Bluteau O., Jeannot E., Bioulac-Sage P., Marques J.M., Blanc J.-F.,
RA Bui H., Beaudoin J.-C., Franco D., Balabaud C., Laurent-Puig P.,
RA Zucman-Rossi J.;
RT "Bi-allelic inactivation of TCF1 in hepatic adenomas.";
RL Nat. Genet. 32:312-315(2002).
RN [34]
RP VARIANT [LARGE SCALE ANALYSIS] GLU-273.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S.,
RA Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J.,
RA Dawson D., Willson J.K.V., Gazdar A.F., Hartigan J., Wu L., Liu C.,
RA Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N.,
RA Vogelstein B., Kinzler K.W., Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal
RT cancers.";
RL Science 314:268-274(2006).
CC -!- FUNCTION: Transcriptional activator that regulates the tissue
CC specific expression of multiple genes, especially in pancreatic
CC islet cells and in liver. Required for the expression of several
CC liver specific genes. Binds to the inverted palindrome 5'-
CC GTTAATNATTAAC-3'.
CC -!- SUBUNIT: Binds DNA as a dimer. Interacts with PCBD1.
CC Heterotetramer with PCBD1; formed by a dimer of dimers.
CC -!- INTERACTION:
CC Q9Y463:DYRK1B; NbExp=4; IntAct=EBI-636034, EBI-634187;
CC -!- SUBCELLULAR LOCATION: Nucleus.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=A;
CC IsoId=P20823-1; Sequence=Displayed;
CC Name=B;
CC IsoId=P20823-2; Sequence=VSP_002250, VSP_002251;
CC Name=C;
CC IsoId=P20823-3; Sequence=VSP_002252, VSP_002253;
CC -!- TISSUE SPECIFICITY: Liver.
CC -!- POLYMORPHISM: The Ala-98/Val-98 polymorphism is associated with a
CC reduction in glucose-induced serum C-peptide and insulin
CC responses.
CC -!- DISEASE: Hepatic adenomas familial (HEPAF) [MIM:142330]: Rare
CC benign liver tumors of presumable epithelial origin that develop
CC in an otherwise normal liver. Hepatic adenomas may be single or
CC multiple. They consist of sheets of well-differentiated
CC hepatocytes that contain fat and glycogen and can produce bile.
CC Bile ducts or portal areas are absent. Kupffer cells, if present,
CC are reduced in number and are non-functional. Conditions
CC associated with adenomas are insulin-dependent diabetes mellitus
CC and glycogen storage diseases (types 1 and 3). Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC Bi-allelic inactivation of HNF1A, whether sporadic or associated
CC with MODY3, may be an early step in the developmant of some
CC hepatocellular carcinomas.
CC -!- DISEASE: Maturity-onset diabetes of the young 3 (MODY3)
CC [MIM:600496]: A form of diabetes that is characterized by an
CC autosomal dominant mode of inheritance, onset in childhood or
CC early adulthood (usually before 25 years of age), a primary defect
CC in insulin secretion and frequent insulin-independence at the
CC beginning of the disease. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- DISEASE: Diabetes mellitus, insulin-dependent, 20 (IDDM20)
CC [MIM:612520]: A multifactorial disorder of glucose homeostasis
CC that is characterized by susceptibility to ketoacidosis in the
CC absence of insulin therapy. Clinical fetaures are polydipsia,
CC polyphagia and polyuria which result from hyperglycemia-induced
CC osmotic diuresis and secondary thirst. These derangements result
CC in long-term complications that affect the eyes, kidneys, nerves,
CC and blood vessels. Note=Disease susceptibility is associated with
CC variations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the HNF1 homeobox family.
CC -!- SIMILARITY: Contains 1 homeobox DNA-binding domain.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/HNF1A";
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Hepatocyte nuclear factors
CC entry;
CC URL="http://en.wikipedia.org/wiki/Hepatocyte_nuclear_factors";
CC -!- WEB RESOURCE: Name=SeattleSNPs;
CC URL="http://pga.gs.washington.edu/data/tcf1/";
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DR EMBL; M57732; AAA88077.1; -; mRNA.
DR EMBL; X71346; CAB59201.1; -; mRNA.
DR EMBL; U72618; AAC51137.1; -; Genomic_DNA.
DR EMBL; U72612; AAC51137.1; JOINED; Genomic_DNA.
DR EMBL; U72613; AAC51137.1; JOINED; Genomic_DNA.
DR EMBL; U72614; AAC51137.1; JOINED; Genomic_DNA.
DR EMBL; U72615; AAC51137.1; JOINED; Genomic_DNA.
DR EMBL; U72616; AAC51137.1; JOINED; Genomic_DNA.
DR EMBL; U72617; AAC51137.1; JOINED; Genomic_DNA.
DR EMBL; EF641294; ABR09270.1; -; Genomic_DNA.
DR EMBL; AC079602; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471054; EAW98226.1; -; Genomic_DNA.
DR EMBL; BC104908; AAI04909.1; -; mRNA.
DR EMBL; BC104910; AAI04911.1; -; mRNA.
DR IPI; IPI00025839; -.
DR IPI; IPI00219056; -.
DR IPI; IPI00411416; -.
DR PIR; A36749; A36749.
DR RefSeq; NP_000536.5; NM_000545.5.
DR UniGene; Hs.654455; -.
DR PDB; 1IC8; X-ray; 2.60 A; A/B=85-278.
DR PDB; 2GYP; X-ray; 1.40 A; A/B=2-32.
DR PDBsum; 1IC8; -.
DR PDBsum; 2GYP; -.
DR ProteinModelPortal; P20823; -.
DR DIP; DIP-33544N; -.
DR IntAct; P20823; 7.
DR STRING; 9606.ENSP00000257555; -.
DR PhosphoSite; P20823; -.
DR DMDM; 51338763; -.
DR PaxDb; P20823; -.
DR PRIDE; P20823; -.
DR DNASU; 6927; -.
DR Ensembl; ENST00000257555; ENSP00000257555; ENSG00000135100.
DR GeneID; 6927; -.
DR KEGG; hsa:6927; -.
DR UCSC; uc001tzg.3; human.
DR CTD; 6927; -.
DR GeneCards; GC12P121416; -.
DR H-InvDB; HIX0036847; -.
DR HGNC; HGNC:11621; HNF1A.
DR HPA; CAB010430; -.
DR MIM; 142330; phenotype.
DR MIM; 142410; gene.
DR MIM; 600496; phenotype.
DR MIM; 606391; phenotype.
DR MIM; 612520; phenotype.
DR neXtProt; NX_P20823; -.
DR Orphanet; 324575; Hyperinsulinism due to HNF1A deficiency.
DR Orphanet; 552; MODY syndrome.
DR PharmGKB; PA36380; -.
DR eggNOG; NOG79356; -.
DR HOGENOM; HOG000015305; -.
DR HOVERGEN; HBG005980; -.
DR InParanoid; P20823; -.
DR KO; K08036; -.
DR OrthoDB; EOG4WH8M1; -.
DR Pathway_Interaction_DB; wnt_canonical_pathway; Canonical Wnt signaling pathway.
DR Pathway_Interaction_DB; hnf3bpathway; FOXA2 and FOXA3 transcription factor networks.
DR Pathway_Interaction_DB; ps1pathway; Presenilin action in Notch and Wnt signaling.
DR SignaLink; P20823; -.
DR EvolutionaryTrace; P20823; -.
DR GenomeRNAi; 6927; -.
DR NextBio; 27105; -.
DR ArrayExpress; P20823; -.
DR Bgee; P20823; -.
DR CleanEx; HS_HNF1A; -.
DR Genevestigator; P20823; -.
DR GermOnline; ENSG00000135100; Homo sapiens.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0001750; C:photoreceptor outer segment; IEA:Compara.
DR GO; GO:0045120; C:pronucleus; IEA:Compara.
DR GO; GO:0043234; C:protein complex; IDA:UniProtKB.
DR GO; GO:0005667; C:transcription factor complex; IEA:Compara.
DR GO; GO:0003677; F:DNA binding; IDA:UniProtKB.
DR GO; GO:0003690; F:double-stranded DNA binding; IEA:Compara.
DR GO; GO:0046982; F:protein heterodimerization activity; IDA:UniProtKB.
DR GO; GO:0001077; F:RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity involved in positive regulation of transcription; ISS:BHF-UCL.
DR GO; GO:0043565; F:sequence-specific DNA binding; IEA:Compara.
DR GO; GO:0003700; F:sequence-specific DNA binding transcription factor activity; IDA:UniProtKB.
DR GO; GO:0044212; F:transcription regulatory region DNA binding; IDA:UniProtKB.
DR GO; GO:0015721; P:bile acid and bile salt transport; IEA:Compara.
DR GO; GO:0006699; P:bile acid biosynthetic process; IEA:Compara.
DR GO; GO:0001824; P:blastocyst development; IEA:Compara.
DR GO; GO:0045453; P:bone resorption; IEA:Compara.
DR GO; GO:0008203; P:cholesterol metabolic process; IEA:Compara.
DR GO; GO:0006338; P:chromatin remodeling; IEA:Compara.
DR GO; GO:0030326; P:embryonic limb morphogenesis; IEA:Compara.
DR GO; GO:0031018; P:endocrine pancreas development; IEA:Compara.
DR GO; GO:0006633; P:fatty acid biosynthetic process; IEA:Compara.
DR GO; GO:0015908; P:fatty acid transport; IEA:Compara.
DR GO; GO:0042593; P:glucose homeostasis; IMP:UniProtKB.
DR GO; GO:0046323; P:glucose import; IMP:UniProtKB.
DR GO; GO:0006783; P:heme biosynthetic process; IEA:Compara.
DR GO; GO:0030073; P:insulin secretion; IEA:Compara.
DR GO; GO:0001889; P:liver development; IEA:Compara.
DR GO; GO:0000122; P:negative regulation of transcription from RNA polymerase II promoter; IEA:Compara.
DR GO; GO:0048341; P:paraxial mesoderm formation; IEA:Compara.
DR GO; GO:0001890; P:placenta development; IEA:Compara.
DR GO; GO:0060261; P:positive regulation of transcription initiation from RNA polymerase II promoter; IGI:UniProtKB.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-dependent; IDA:UniProtKB.
DR GO; GO:0008104; P:protein localization; IEA:Compara.
DR GO; GO:0050796; P:regulation of insulin secretion; IEA:Compara.
DR GO; GO:0030111; P:regulation of Wnt receptor signaling pathway; IEA:Compara.
DR GO; GO:0035623; P:renal glucose absorption; IMP:UniProtKB.
DR GO; GO:0048608; P:reproductive structure development; IEA:Compara.
DR GO; GO:0009749; P:response to glucose stimulus; IEA:Compara.
DR GO; GO:0006979; P:response to oxidative stress; IEA:Compara.
DR GO; GO:0043691; P:reverse cholesterol transport; IEA:Compara.
DR GO; GO:0060395; P:SMAD protein signal transduction; IEA:Compara.
DR Gene3D; 1.10.10.60; -; 1.
DR Gene3D; 1.10.260.40; -; 1.
DR InterPro; IPR006899; HNF-1_N.
DR InterPro; IPR023219; HNF1_dimer_dom.
DR InterPro; IPR006898; HNF1a_C.
DR InterPro; IPR006897; HNF1b_C.
DR InterPro; IPR001356; Homeodomain.
DR InterPro; IPR009057; Homeodomain-like.
DR InterPro; IPR010982; Lambda_DNA-bd_dom.
DR Pfam; PF04814; HNF-1_N; 1.
DR Pfam; PF04813; HNF-1A_C; 1.
DR Pfam; PF04812; HNF-1B_C; 1.
DR Pfam; PF00046; Homeobox; 1.
DR SMART; SM00389; HOX; 1.
DR SUPFAM; SSF100957; HNF1_dimer_dom; 1.
DR SUPFAM; SSF46689; Homeodomain_like; 1.
DR SUPFAM; SSF47413; Lambda_like_DNA; 1.
DR PROSITE; PS00027; HOMEOBOX_1; 1.
DR PROSITE; PS50071; HOMEOBOX_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Activator; Alternative splicing; Complete proteome;
KW Diabetes mellitus; Disease mutation; DNA-binding; Homeobox; Nucleus;
KW Phosphoprotein; Polymorphism; Reference proteome; Transcription;
KW Transcription regulation.
FT CHAIN 1 631 Hepatocyte nuclear factor 1-alpha.
FT /FTId=PRO_0000049115.
FT DNA_BIND 199 279 Homeobox; HNF1-type.
FT REGION 1 31 Dimerization.
FT REGION 130 132 Interaction with DNA.
FT REGION 143 149 Interaction with DNA.
FT REGION 155 158 Interaction with DNA.
FT REGION 203 206 Interaction with DNA.
FT REGION 263 265 Interaction with DNA.
FT REGION 270 273 Interaction with DNA.
FT MOTIF 197 205 Nuclear localization signal (Probable).
FT COMPBIAS 71 80 Asp/Glu-rich (acidic; potential
FT involvement with transcription).
FT MOD_RES 74 74 Phosphothreonine (By similarity).
FT MOD_RES 247 247 Phosphoserine (By similarity).
FT VAR_SEQ 438 494 LASTQAQSVPVINSMGSSLTTLQPVQFSQPLHPSYQQPLMP
FT PVQSHVTQSPFMATMA -> KLVGMGGHLGGRLMGQPQNPG
FT AGRATGTHSFIHSFIQHVFIQCLLWTSHCATSVIPG (in
FT isoform C).
FT /FTId=VSP_002252.
FT VAR_SEQ 495 601 Missing (in isoform C).
FT /FTId=VSP_002253.
FT VAR_SEQ 501 542 ALYSHKPEVAQYTHTGLLPQTMLITDTTNLSALASLTPTKQ
FT V -> GEHPVPHTAGDDDRGWLSMDAGERGAWQALQSACVS
FT GTSVFP (in isoform B).
FT /FTId=VSP_002250.
FT VAR_SEQ 543 601 Missing (in isoform B).
FT /FTId=VSP_002251.
FT VARIANT 12 12 L -> H (in MODY3; abolishes interaction
FT with PCBD1 and DNA).
FT /FTId=VAR_010537.
FT VARIANT 20 20 G -> R (in MODY3; abolishes interaction
FT with PCBD1 and DNA).
FT /FTId=VAR_012483.
FT VARIANT 27 27 I -> L (in dbSNP:rs1169288).
FT /FTId=VAR_007905.
FT VARIANT 31 31 G -> D (in MODY3; no effect on
FT interaction with PCBD1 and DNA).
FT /FTId=VAR_010538.
FT VARIANT 48 48 E -> K (in IDDM20).
FT /FTId=VAR_010539.
FT VARIANT 98 98 A -> V (in dbSNP:rs1800574).
FT /FTId=VAR_010540.
FT VARIANT 107 107 L -> R (in MODY3).
FT /FTId=VAR_010541.
FT VARIANT 117 117 K -> E (in MODY3).
FT /FTId=VAR_010542.
FT VARIANT 122 122 Y -> C (in MODY3).
FT /FTId=VAR_003756.
FT VARIANT 127 127 N -> Y (in a hepatocellular carcinoma
FT sample; somatic mutation).
FT /FTId=VAR_033088.
FT VARIANT 128 128 I -> N (in MODY3).
FT /FTId=VAR_010543.
FT VARIANT 129 129 P -> T (in MODY3).
FT /FTId=VAR_010544.
FT VARIANT 131 131 R -> Q (in MODY3; expected to interfere
FT with DNA binding).
FT /FTId=VAR_010545.
FT VARIANT 131 131 R -> W (in MODY3; expected to interfere
FT with DNA binding).
FT /FTId=VAR_010546.
FT VARIANT 133 133 V -> M (in MODY3).
FT /FTId=VAR_010547.
FT VARIANT 142 142 S -> F (in MODY3; reduces transcription
FT activation by about 80%).
FT /FTId=VAR_003757.
FT VARIANT 143 143 H -> Y (in MODY3; expected to interfere
FT with DNA binding).
FT /FTId=VAR_010548.
FT VARIANT 158 158 K -> N (in MODY3; expected to interfere
FT with DNA binding).
FT /FTId=VAR_010549.
FT VARIANT 159 159 R -> Q (in MODY3).
FT /FTId=VAR_003758.
FT VARIANT 159 159 R -> W (in MODY3).
FT /FTId=VAR_010550.
FT VARIANT 161 161 A -> T (in MODY3).
FT /FTId=VAR_010551.
FT VARIANT 165 165 W -> C (in a hepatocellular carcinoma
FT sample; somatic mutation).
FT /FTId=VAR_033089.
FT VARIANT 191 191 G -> D (in late-onset NIDDM).
FT /FTId=VAR_010552.
FT VARIANT 200 200 R -> W (in MODY3; expected to interfere
FT with nuclear localization).
FT /FTId=VAR_063069.
FT VARIANT 203 203 R -> C (in MODY3; expected to interfere
FT with nuclear localization and DNA
FT binding).
FT /FTId=VAR_010554.
FT VARIANT 203 203 R -> H (in MODY3; expected to interfere
FT with nuclear localization and DNA
FT binding).
FT /FTId=VAR_012484.
FT VARIANT 205 205 K -> Q (in MODY3; reduces transcription
FT activation by about 50%).
FT /FTId=VAR_010555.
FT VARIANT 206 206 W -> C (in a hepatic adenoma sample;
FT somatic mutation; expected to interfere
FT with DNA binding).
FT /FTId=VAR_033090.
FT VARIANT 206 206 W -> L (in a hepatic adenoma sample;
FT somatic mutation; expected to interfere
FT with DNA binding).
FT /FTId=VAR_033091.
FT VARIANT 229 229 R -> Q (in MODY3).
FT /FTId=VAR_010556.
FT VARIANT 237 237 N -> S (in a hepatic multiple adenoma
FT sample; somatic mutation).
FT /FTId=VAR_033092.
FT VARIANT 241 241 C -> G (in IDDM20 and MODY3).
FT /FTId=VAR_010557.
FT VARIANT 244 244 R -> G (in a hepatic adenoma sample;
FT somatic mutation; expected to interfere
FT with DNA binding).
FT /FTId=VAR_033093.
FT VARIANT 250 250 Q -> P (in a hepatocellular carcinoma
FT sample; somatic mutation).
FT /FTId=VAR_033094.
FT VARIANT 254 254 L -> M (in late-onset NIDDM; low
FT penetrance; could be a rare
FT polymorphism).
FT /FTId=VAR_010558.
FT VARIANT 259 259 V -> D (in MODY3).
FT /FTId=VAR_010559.
FT VARIANT 260 260 T -> M (in MODY3).
FT /FTId=VAR_010560.
FT VARIANT 263 263 R -> C (in MODY3; expected to interfere
FT with DNA binding).
FT /FTId=VAR_010561.
FT VARIANT 268 268 F -> C (in a hepatic adenoma sample;
FT somatic mutation).
FT /FTId=VAR_033095.
FT VARIANT 271 271 R -> W (in MODY3).
FT /FTId=VAR_010562.
FT VARIANT 272 272 R -> C (in NIDDM).
FT /FTId=VAR_010563.
FT VARIANT 272 272 R -> H (in IDDM20 and MODY3).
FT /FTId=VAR_003759.
FT VARIANT 273 273 K -> E (in a hepatic adenoma sample;
FT somatic mutation).
FT /FTId=VAR_033096.
FT VARIANT 319 319 G -> S (strong association with NIDDM
FT susceptibility; unique to the Canadian
FT Oji-Cree population).
FT /FTId=VAR_010564.
FT VARIANT 415 415 G -> R (in IDDM20; loss of function).
FT /FTId=VAR_010565.
FT VARIANT 432 432 S -> C (in MODY3).
FT /FTId=VAR_012485.
FT VARIANT 447 447 P -> L (in MODY3).
FT /FTId=VAR_003760.
FT VARIANT 487 487 S -> N (in dbSNP:rs2464196).
FT /FTId=VAR_007906.
FT VARIANT 514 514 H -> R.
FT /FTId=VAR_010566.
FT VARIANT 519 519 P -> L (in MODY3).
FT /FTId=VAR_010567.
FT VARIANT 537 537 T -> R (in MODY3; incomplete penetrance).
FT /FTId=VAR_010568.
FT VARIANT 574 574 G -> S (in a black African with an
FT atypical form of diabetes; also in an
FT individual with hepatic adenoma and
FT familial early-onset diabetes;
FT dbSNP:rs1169305).
FT /FTId=VAR_010569.
FT VARIANT 583 583 R -> G (in IDDM20).
FT /FTId=VAR_003761.
FT VARIANT 583 583 R -> Q (in late-onset NIDDM; also in an
FT individual with hepatic hyperplasia and
FT familial early-onset diabetes).
FT /FTId=VAR_010570.
FT VARIANT 594 594 S -> I (in MODY3).
FT /FTId=VAR_010571.
FT VARIANT 618 618 I -> M (in MODY3).
FT /FTId=VAR_012486.
FT VARIANT 619 619 E -> K (in MODY3).
FT /FTId=VAR_010572.
FT VARIANT 620 620 T -> I (in MODY3; incomplete penetrance).
FT /FTId=VAR_010573.
FT MUTAGEN 127 127 N->W: Abolishes transcription activation.
FT MUTAGEN 132 132 E->K: Abolishes transcription activation.
FT MUTAGEN 177 177 F->S: No significant effect on
FT transcription activation.
FT MUTAGEN 186 186 I->Q: No effect on transcription
FT activation.
FT MUTAGEN 190 190 T->Q: No effect on transcription
FT activation.
FT MUTAGEN 202 202 N->D: Reduces transcription activation by
FT 70%.
FT MUTAGEN 246 246 V->D: Reduces transcription activation by
FT 75%.
FT MUTAGEN 257 257 N->W: Reduces transcription activation by
FT 70%.
FT HELIX 4 19
FT HELIX 23 30
FT HELIX 94 107
FT HELIX 112 125
FT HELIX 130 137
FT HELIX 141 149
FT HELIX 156 169
FT TURN 170 173
FT HELIX 174 177
FT HELIX 208 221
FT TURN 226 229
FT HELIX 230 243
FT HELIX 255 257
FT HELIX 261 274
SQ SEQUENCE 631 AA; 67356 MW; 8327CD4FDC39254A CRC64;
MVSKLSQLQT ELLAALLESG LSKEALIQAL GEPGPYLLAG EGPLDKGESC GGGRGELAEL
PNGLGETRGS EDETDDDGED FTPPILKELE NLSPEEAAHQ KAVVETLLQE DPWRVAKMVK
SYLQQHNIPQ REVVDTTGLN QSHLSQHLNK GTPMKTQKRA ALYTWYVRKQ REVAQQFTHA
GQGGLIEEPT GDELPTKKGR RNRFKWGPAS QQILFQAYER QKNPSKEERE TLVEECNRAE
CIQRGVSPSQ AQGLGSNLVT EVRVYNWFAN RRKEEAFRHK LAMDTYSGPP PGPGPGPALP
AHSSPGLPPP ALSPSKVHGV RYGQPATSET AEVPSSSGGP LVTVSTPLHQ VSPTGLEPSH
SLLSTEAKLV SAAGGPLPPV STLTALHSLE QTSPGLNQQP QNLIMASLPG VMTIGPGEPA
SLGPTFTNTG ASTLVIGLAS TQAQSVPVIN SMGSSLTTLQ PVQFSQPLHP SYQQPLMPPV
QSHVTQSPFM ATMAQLQSPH ALYSHKPEVA QYTHTGLLPQ TMLITDTTNL SALASLTPTK
QVFTSDTEAS SESGLHTPAS QATTLHVPSQ DPAGIQHLQP AHRLSASPTV SSSSLVLYQS
SDSSNGQSHL LPSNHSVIET FISTQMASSS Q
//
