ID NIPA4_HUMAN Reviewed; 404 AA.
AC Q0D2K0; A8S6F1; A8S6F5; A8S6F8; B4DLF3; Q0D2J8; Q0D2J9;
DT 17-APR-2007, integrated into UniProtKB/Swiss-Prot.
DT 23-FEB-2022, sequence version 4.
DT 24-JAN-2024, entry version 131.
DE RecName: Full=Magnesium transporter NIPA4;
DE AltName: Full=Ichthyin;
DE AltName: Full=NIPA-like protein 4;
DE AltName: Full=Non-imprinted in Prader-Willi/Angelman syndrome region protein 4;
GN Name=NIPAL4; Synonyms=ICHN, NIPA4;
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 [GENOMIC DNA] (ISOFORM 1), TISSUE SPECIFICITY, AND
RP VARIANTS ARCI6 ASP-114 AND ARG-168.
RX PubMed=17557927; DOI=10.1136/jmg.2007.050542;
RA Dahlqvist J., Klar J., Hausser I., Anton-Lamprecht I., Pigg M.H.,
RA Gedde-Dahl T., Gaanemo A., Vahlquist A., Dahl N.;
RT "Congenital ichthyosis: mutations in ichthyin are associated with specific
RT structural abnormalities in the granular layer of epidermis.";
RL J. Med. Genet. 44:615-620(2007).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Tongue;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15372022; DOI=10.1038/nature02919;
RA Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S.,
RA Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M.,
RA She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S.,
RA Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M.,
RA Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T., Gomez M.,
RA Gonzales E., Goodstein D., Grigoriev I., Groza M., Hammon N., Hawkins T.,
RA Haydu L., Israni S., Jett J., Kadner K., Kimball H., Kobayashi A.,
RA Lopez F., Lou Y., Martinez D., Medina C., Morgan J., Nandkeshwar R.,
RA Noonan J.P., Pitluck S., Pollard M., Predki P., Priest J., Ramirez L.,
RA Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., Thayer N.,
RA Tice H., Tsai M., Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J.,
RA Dickson M., Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A.,
RA Rokhsar D.S., Richardson P., Lucas S.M., Myers R.M., Rubin E.M.;
RT "The DNA sequence and comparative analysis of human chromosome 5.";
RL Nature 431:268-274(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 55-404 (ISOFORM 1).
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 project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [5]
RP VARIANTS ARCI6 VAL-80; ASP-114; PHE-146; ASN-175 AND ARG-235, FUNCTION, AND
RP TISSUE SPECIFICITY.
RX PubMed=15317751; DOI=10.1093/hmg/ddh263;
RA Lefevre C., Bouadjar B., Karaduman A., Jobard F., Saker S., Ozguc M.,
RA Lathrop M., Prud'homme J.-F., Fischer J.;
RT "Mutations in ichthyin a new gene on chromosome 5q33 in a new form of
RT autosomal recessive congenital ichthyosis.";
RL Hum. Mol. Genet. 13:2473-2482(2004).
RN [6]
RP VARIANT ARCI6 ARG-73.
RX PubMed=26456858; DOI=10.1111/ced.12740;
RA Maier D., Mazereeuw-Hautier J., Tilinca M., Cosgarea R., Jonca N.;
RT "Novel mutation in NIPAL4 in a Romanian family with autosomal recessive
RT congenital ichthyosis.";
RL Clin. Exp. Dermatol. 41:279-282(2016).
CC -!- FUNCTION: Acts as a Mg(2+) transporter. Can also transport other
CC divalent cations such as Ba(2+), Sr(2+) and Fe(2+) but to a much less
CC extent than Mg(2+) (By similarity). May be a receptor for ligands
CC (trioxilins A3 and B3) from the hepoxilin pathway (PubMed:15317751).
CC {ECO:0000250|UniProtKB:Q8BZF2, ECO:0000269|PubMed:15317751}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=Mg(2+)(in) = Mg(2+)(out); Xref=Rhea:RHEA:29827,
CC ChEBI:CHEBI:18420; Evidence={ECO:0000250|UniProtKB:Q8BZF2};
CC -!- INTERACTION:
CC Q0D2K0; O00590: ACKR2; NbExp=3; IntAct=EBI-9550165, EBI-13379418;
CC Q0D2K0; O95471: CLDN7; NbExp=3; IntAct=EBI-9550165, EBI-740744;
CC Q0D2K0; Q8TAZ6: CMTM2; NbExp=3; IntAct=EBI-9550165, EBI-2339374;
CC Q0D2K0; P21964: COMT; NbExp=3; IntAct=EBI-9550165, EBI-372265;
CC Q0D2K0; O15552: FFAR2; NbExp=3; IntAct=EBI-9550165, EBI-2833872;
CC Q0D2K0; P08034: GJB1; NbExp=3; IntAct=EBI-9550165, EBI-17565645;
CC Q0D2K0; Q8TDT2: GPR152; NbExp=3; IntAct=EBI-9550165, EBI-13345167;
CC Q0D2K0; Q9UM44: HHLA2; NbExp=3; IntAct=EBI-9550165, EBI-2867874;
CC Q0D2K0; Q13651: IL10RA; NbExp=3; IntAct=EBI-9550165, EBI-1031656;
CC Q0D2K0; Q8TAF8: LHFPL5; NbExp=3; IntAct=EBI-9550165, EBI-2820517;
CC Q0D2K0; Q96GF1: RNF185; NbExp=3; IntAct=EBI-9550165, EBI-2340249;
CC Q0D2K0; Q6ZMZ0: RNF19B; NbExp=3; IntAct=EBI-9550165, EBI-2466594;
CC Q0D2K0; Q8WWF3: SSMEM1; NbExp=3; IntAct=EBI-9550165, EBI-17280858;
CC Q0D2K0; Q96CE8: TM4SF18; NbExp=3; IntAct=EBI-9550165, EBI-13351685;
CC Q0D2K0; P34981: TRHR; NbExp=3; IntAct=EBI-9550165, EBI-18055230;
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250|UniProtKB:Q9JJC8};
CC Multi-pass membrane protein {ECO:0000255}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q0D2K0-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q0D2K0-2; Sequence=VSP_036122;
CC -!- TISSUE SPECIFICITY: Highly expressed in brain, lung, stomach,
CC keratinocytes and leukocytes, and in all other tissues tested except
CC liver, thyroid and fetal brain. {ECO:0000269|PubMed:15317751,
CC ECO:0000269|PubMed:17557927}.
CC -!- DISEASE: Ichthyosis, congenital, autosomal recessive 6 (ARCI6)
CC [MIM:612281]: A form of autosomal recessive congenital ichthyosis, a
CC disorder of keratinization with abnormal differentiation and
CC desquamation of the epidermis, resulting in abnormal skin scaling over
CC the whole body. The main skin phenotypes are lamellar ichthyosis (LI)
CC and non-bullous congenital ichthyosiform erythroderma (NCIE), although
CC phenotypic overlap within the same patient or among patients from the
CC same family can occur. Lamellar ichthyosis is a condition often
CC associated with an embedment in a collodion-like membrane at birth;
CC skin scales later develop, covering the entire body surface. Non-
CC bullous congenital ichthyosiform erythroderma characterized by fine
CC whitish scaling on an erythrodermal background; larger brownish scales
CC are present on the buttocks, neck and legs.
CC {ECO:0000269|PubMed:15317751, ECO:0000269|PubMed:17557927,
CC ECO:0000269|PubMed:26456858}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the NIPA family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=ABW69628.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
CC Sequence=ABW69629.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
CC Sequence=ABW69630.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
CC Sequence=ABW69630.1; Type=Miscellaneous discrepancy; Note=Protein truncation is due to an exon 5 splice site mutation which is found in a ARCII patient.; Evidence={ECO:0000305};
CC Sequence=BAG59515.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; EF599763; ABW69628.1; ALT_INIT; Genomic_DNA.
DR EMBL; EF599764; ABW69629.1; ALT_INIT; Genomic_DNA.
DR EMBL; EF599765; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; EF599766; ABW69630.1; ALT_SEQ; Genomic_DNA.
DR EMBL; AK296972; BAG59515.1; ALT_INIT; mRNA.
DR EMBL; AC008676; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC105708; AAI05709.1; -; mRNA.
DR EMBL; BC105709; AAI05710.1; -; mRNA.
DR EMBL; BC105710; AAI05711.1; -; mRNA.
DR CCDS; CCDS47328.2; -. [Q0D2K0-1]
DR CCDS; CCDS54944.1; -. [Q0D2K0-2]
DR RefSeq; NP_001092757.1; NM_001099287.1. [Q0D2K0-1]
DR RefSeq; NP_001165763.1; NM_001172292.1. [Q0D2K0-2]
DR AlphaFoldDB; Q0D2K0; -.
DR BioGRID; 131541; 22.
DR IntAct; Q0D2K0; 17.
DR STRING; 9606.ENSP00000311687; -.
DR TCDB; 2.A.7.25.4; the drug/metabolite transporter (dmt) superfamily.
DR GlyCosmos; Q0D2K0; 3 sites, No reported glycans.
DR GlyGen; Q0D2K0; 3 sites.
DR iPTMnet; Q0D2K0; -.
DR PhosphoSitePlus; Q0D2K0; -.
DR BioMuta; NIPAL4; -.
DR DMDM; 221222524; -.
DR EPD; Q0D2K0; -.
DR MassIVE; Q0D2K0; -.
DR MaxQB; Q0D2K0; -.
DR PaxDb; 9606-ENSP00000311687; -.
DR PeptideAtlas; Q0D2K0; -.
DR ProteomicsDB; 58743; -. [Q0D2K0-1]
DR ProteomicsDB; 58744; -. [Q0D2K0-2]
DR Antibodypedia; 48488; 87 antibodies from 16 providers.
DR DNASU; 348938; -.
DR Ensembl; ENST00000311946.8; ENSP00000311687.8; ENSG00000172548.15. [Q0D2K0-1]
DR Ensembl; ENST00000435489.7; ENSP00000406456.3; ENSG00000172548.15. [Q0D2K0-2]
DR GeneID; 348938; -.
DR KEGG; hsa:348938; -.
DR MANE-Select; ENST00000311946.8; ENSP00000311687.8; NM_001099287.2; NP_001092757.2.
DR UCSC; uc003lwx.5; human. [Q0D2K0-1]
DR AGR; HGNC:28018; -.
DR CTD; 348938; -.
DR DisGeNET; 348938; -.
DR GeneCards; NIPAL4; -.
DR GeneReviews; NIPAL4; -.
DR HGNC; HGNC:28018; NIPAL4.
DR HPA; ENSG00000172548; Tissue enhanced (brain, skin).
DR MalaCards; NIPAL4; -.
DR MIM; 609383; gene.
DR MIM; 612281; phenotype.
DR neXtProt; NX_Q0D2K0; -.
DR OpenTargets; ENSG00000172548; -.
DR Orphanet; 79394; Congenital ichthyosiform erythroderma.
DR Orphanet; 313; Lamellar ichthyosis.
DR PharmGKB; PA164723956; -.
DR VEuPathDB; HostDB:ENSG00000172548; -.
DR eggNOG; KOG2922; Eukaryota.
DR GeneTree; ENSGT00940000159087; -.
DR HOGENOM; CLU_012349_1_2_1; -.
DR InParanoid; Q0D2K0; -.
DR OrthoDB; 53219at2759; -.
DR PhylomeDB; Q0D2K0; -.
DR TreeFam; TF313214; -.
DR PathwayCommons; Q0D2K0; -.
DR Reactome; R-HSA-5223345; Miscellaneous transport and binding events.
DR SignaLink; Q0D2K0; -.
DR BioGRID-ORCS; 348938; 8 hits in 1141 CRISPR screens.
DR GenomeRNAi; 348938; -.
DR Pharos; Q0D2K0; Tbio.
DR PRO; PR:Q0D2K0; -.
DR Proteomes; UP000005640; Chromosome 5.
DR RNAct; Q0D2K0; Protein.
DR Bgee; ENSG00000172548; Expressed in upper arm skin and 132 other cell types or tissues.
DR ExpressionAtlas; Q0D2K0; baseline and differential.
DR Genevisible; Q0D2K0; HS.
DR GO; GO:0016020; C:membrane; IBA:GO_Central.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0015095; F:magnesium ion transmembrane transporter activity; IEA:InterPro.
DR GO; GO:0015693; P:magnesium ion transport; IBA:GO_Central.
DR InterPro; IPR008521; Mg_trans_NIPA.
DR PANTHER; PTHR12570:SF7; MAGNESIUM TRANSPORTER NIPA4; 1.
DR PANTHER; PTHR12570; UNCHARACTERIZED; 1.
DR Pfam; PF05653; Mg_trans_NIPA; 1.
DR SUPFAM; SSF103481; Multidrug resistance efflux transporter EmrE; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Cell membrane; Disease variant; Glycoprotein;
KW Ichthyosis; Ion transport; Magnesium; Membrane; Receptor;
KW Reference proteome; Transmembrane; Transmembrane helix; Transport.
FT CHAIN 1..404
FT /note="Magnesium transporter NIPA4"
FT /id="PRO_0000284447"
FT TOPO_DOM 1..55
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 56..76
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 77..102
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 103..123
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 124
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 125..145
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 146..153
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 154..174
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 175..195
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 196..216
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 217..223
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 224..244
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 245..261
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 262..282
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 283..293
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 294..314
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 315..324
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 325..345
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 346..404
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT CARBOHYD 7
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 12
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 40
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT VAR_SEQ 94..112
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_036122"
FT VARIANT 73
FT /note="S -> R (in ARCI6; dbSNP:rs376803325)"
FT /evidence="ECO:0000269|PubMed:26456858"
FT /id="VAR_075461"
FT VARIANT 80
FT /note="G -> V (in ARCI6; dbSNP:rs775903553)"
FT /evidence="ECO:0000269|PubMed:15317751"
FT /id="VAR_031736"
FT VARIANT 114
FT /note="A -> D (in ARCI6; frequent mutation;
FT dbSNP:rs199422217)"
FT /evidence="ECO:0000269|PubMed:15317751,
FT ECO:0000269|PubMed:17557927"
FT /id="VAR_031737"
FT VARIANT 146
FT /note="S -> F (in ARCI6)"
FT /evidence="ECO:0000269|PubMed:15317751"
FT /id="VAR_031738"
FT VARIANT 168
FT /note="G -> R (in ARCI6; dbSNP:rs370356566)"
FT /evidence="ECO:0000269|PubMed:17557927"
FT /id="VAR_054120"
FT VARIANT 175
FT /note="H -> N (in ARCI6)"
FT /evidence="ECO:0000269|PubMed:15317751"
FT /id="VAR_031739"
FT VARIANT 235
FT /note="G -> R (in ARCI6; dbSNP:rs375688767)"
FT /evidence="ECO:0000269|PubMed:15317751"
FT /id="VAR_031740"
FT CONFLICT 151
FT /note="R -> G (in Ref. 2; BAG59515 and 4; AAI05711)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 404 AA; 44005 MW; 67D97A2881CE508A CRC64;
MELRVSNTSC ENGSLLHLYC SSQEVLCQIV NDLSPEVPSN ATFHSWQERI RQNYGFYIGL
GLAFLSSFLI GSSVILKKKG LLRLVATGAT RAVDGGFGYL KDAMWWAGFL TMAAGEVANF
GAYAFAPATV VTPLGALSVL ISAILSSYFL RESLNLLGKL GCVICVAGST VMVIHAPEEE
KVTTIMEMAS KMKDTGFIVF AVLLLVSCLI LIFVIAPRYG QRNILIYIII CSVIGAFSVA
AVKGLGITIK NFFQGLPVVR HPLPYILSLI LALSLSTQVN FLNRALDIFN TSLVFPIYYV
FFTTVVVTSS IILFKEWYSM SAVDIAGTLS GFVTIILGVF MLHAFKDLDI SCASLPHMHK
NPPPSPAPEP TVIRLEDKNV LVDNIELAST SSPEEKPKVF IIHS
//
