RBCC Red Blood Cell Collection

AP1S1 (AP19, CLAPS1) [Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
AP-1 complex subunit sigma-1A (Adapter-related protein complex 1 subunit sigma-1A; Adaptor protein complex AP-1 subunit sigma-1A; Clathrin assembly protein complex 1 sigma-1A small chain; Clathrin coat assembly protein AP19; Golgi adaptor HA1/AP1 adaptin sigma-1A subunit; HA1 19 kDa subunit; Sigma 1a subunit of AP-1 clathrin; Sigma-adaptin 1A; Sigma1A-adaptin)

UniProt P61966
ID AP1S1_HUMAN Reviewed; 158 AA.
AC P61966; B2R5D8; P82267; Q00382; Q53YA7; Q9BTN4; Q9UDW9;
DT 07-JUN-2004, integrated into UniProtKB/Swiss-Prot.
read moreDT 07-JUN-2004, sequence version 1.
DT 22-JAN-2014, entry version 97.
DE RecName: Full=AP-1 complex subunit sigma-1A;
DE AltName: Full=Adapter-related protein complex 1 subunit sigma-1A;
DE AltName: Full=Adaptor protein complex AP-1 subunit sigma-1A;
DE AltName: Full=Clathrin assembly protein complex 1 sigma-1A small chain;
DE AltName: Full=Clathrin coat assembly protein AP19;
DE AltName: Full=Golgi adaptor HA1/AP1 adaptin sigma-1A subunit;
DE AltName: Full=HA1 19 kDa subunit;
DE AltName: Full=Sigma 1a subunit of AP-1 clathrin;
DE AltName: Full=Sigma-adaptin 1A;
DE AltName: Full=Sigma1A-adaptin;
GN Name=AP1S1; Synonyms=AP19, CLAPS1;
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] (ISOFORM 1), FUNCTION, SUBCELLULAR
RP LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=9733768; DOI=10.1074/jbc.273.38.24693;
RA Takatsu H., Sakurai M., Shin H.-W., Murakami K., Nakayama K.;
RT "Identification and characterization of novel clathrin adaptor-related
RT proteins.";
RL J. Biol. Chem. 273:24693-24700(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Caudate nucleus;
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.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA 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.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., 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 [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.,
RA Wylie K., Sekhon M., Becker M.C., O'Laughlin M.D., Schaller M.E.,
RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Cordes M., Du H.,
RA Sun H., Edwards J., Bradshaw-Cordum H., Ali J., Andrews S., Isak A.,
RA Vanbrunt A., Nguyen C., Du F., Lamar B., Courtney L., Kalicki J.,
RA Ozersky P., Bielicki L., Scott K., Holmes A., Harkins R., Harris A.,
RA Strong C.M., Hou S., Tomlinson C., Dauphin-Kohlberg S.,
RA Kozlowicz-Reilly A., Leonard S., Rohlfing T., Rock S.M.,
RA Tin-Wollam A.-M., Abbott A., Minx P., Maupin R., Strowmatt C.,
RA Latreille P., Miller N., Johnson D., Murray J., Woessner J.P.,
RA Wendl M.C., Yang S.-P., Schultz B.R., Wallis J.W., Spieth J.,
RA Bieri T.A., Nelson J.O., Berkowicz N., Wohldmann P.E., Cook L.L.,
RA Hickenbotham M.T., Eldred J., Williams D., Bedell J.A., Mardis E.R.,
RA 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.,
RA Simms E., Levy R., Clendenning J., Kaul R., Kent W.J., Furey T.S.,
RA Baertsch R.A., Brent M.R., Keibler E., Flicek P., Bork P., Suyama M.,
RA Bailey J.A., Portnoy M.E., Torrents D., Chinwalla A.T., Gish W.R.,
RA Eddy S.R., McPherson J.D., Olson M.V., Eichler E.E., Green E.D.,
RA Waterston R.H., 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].
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 [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Placenta;
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 [7]
RP INDUCTION, AND MASS SPECTROMETRY.
RX PubMed=16548883; DOI=10.1111/j.1462-5822.2005.00644.x;
RA Leong W.F., Chow V.T.;
RT "Transcriptomic and proteomic analyses of rhabdomyosarcoma cells
RT reveal differential cellular gene expression in response to
RT enterovirus 71 infection.";
RL Cell. Microbiol. 8:565-580(2006).
RN [8]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-147, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of
RT the kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [9]
RP INVOLVEMENT IN MEDNIK.
RX PubMed=19057675; DOI=10.1371/journal.pgen.1000296;
RA Montpetit A., Cote S., Brustein E., Drouin C.A., Lapointe L.,
RA Boudreau M., Meloche C., Drouin R., Hudson T.J., Drapeau P.,
RA Cossette P.;
RT "Disruption of AP1S1, causing a novel neurocutaneous syndrome,
RT perturbs development of the skin and spinal cord.";
RL PLoS Genet. 4:E1000296-E1000296(2008).
RN [10]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-147, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [12]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
CC -!- FUNCTION: Subunit of clathrin-associated adaptor protein complex 1
CC that plays a role in protein sorting in the late-Golgi/trans-Golgi
CC network (TGN) and/or endosomes. The AP complexes mediate both the
CC recruitment of clathrin to membranes and the recognition of
CC sorting signals within the cytosolic tails of transmembrane cargo
CC molecules.
CC -!- SUBUNIT: Adaptor protein complex 1 (AP-1) is a heterotetramer
CC composed of two large adaptins (gamma-type subunit AP1G1 and beta-
CC type subunit AP1B1), a medium adaptin (mu-type subunit AP1M1 or
CC AP1M2) and a small adaptin (sigma-type subunit AP1S1 or AP1S2 or
CC AP1S3).
CC -!- SUBCELLULAR LOCATION: Golgi apparatus. Cytoplasmic vesicle
CC membrane; Peripheral membrane protein; Cytoplasmic side. Membrane,
CC clathrin-coated pit. Note=Component of the coat surrounding the
CC cytoplasmic face of coated vesicles located at the Golgi complex.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P61966-1, Q00382-1;
CC Sequence=Displayed;
CC Name=2;
CC IsoId=P61966-2, Q00382-2;
CC Sequence=VSP_000171;
CC -!- TISSUE SPECIFICITY: Widely expressed.
CC -!- INDUCTION: Up-regulated in response to enterovirus 71 (EV71)
CC infection.
CC -!- DISEASE: Mental retardation, enteropathy, deafness, peripheral
CC neuropathy, ichthyosis, and keratoderma (MEDNIK) [MIM:609313]: A
CC disorder characterized by erythematous skin lesions and
CC hyperkeratosis, severe psychomotor retardation, peripheral
CC neuropathy, sensorineural hearing loss, together with elevated
CC very-long-chain fatty acids and severe congenital diarrhea.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- SIMILARITY: Belongs to the adaptor complexes small subunit family.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAD45829.1; Type=Erroneous initiation; Note=Translation N-terminally extended;
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DR EMBL; AB015319; BAA33391.1; -; mRNA.
DR EMBL; BT006779; AAP35425.1; -; mRNA.
DR EMBL; AK312151; BAG35085.1; -; mRNA.
DR EMBL; AC004876; AAD45829.1; ALT_INIT; Genomic_DNA.
DR EMBL; CH471197; EAW50199.1; -; Genomic_DNA.
DR EMBL; BC003561; AAH03561.1; -; mRNA.
DR RefSeq; NP_001274.1; NM_001283.3.
DR RefSeq; XP_005250196.1; XM_005250139.1.
DR UniGene; Hs.489365; -.
DR ProteinModelPortal; P61966; -.
DR SMR; P61966; 1-148.
DR MINT; MINT-5006039; -.
DR STRING; 9606.ENSP00000336666; -.
DR PhosphoSite; P61966; -.
DR DMDM; 48428719; -.
DR PaxDb; P61966; -.
DR PRIDE; P61966; -.
DR DNASU; 1174; -.
DR Ensembl; ENST00000337619; ENSP00000336666; ENSG00000106367.
DR Ensembl; ENST00000443943; ENSP00000410780; ENSG00000106367.
DR GeneID; 1174; -.
DR KEGG; hsa:1174; -.
DR UCSC; uc003uxv.4; human.
DR CTD; 1174; -.
DR GeneCards; GC07P100797; -.
DR HGNC; HGNC:559; AP1S1.
DR MIM; 603531; gene.
DR MIM; 609313; phenotype.
DR neXtProt; NX_P61966; -.
DR Orphanet; 171851; MEDNIK syndrome.
DR PharmGKB; PA24850; -.
DR eggNOG; COG5030; -.
DR HOVERGEN; HBG050517; -.
DR InParanoid; P61966; -.
DR KO; K12394; -.
DR OrthoDB; EOG7S7SGC; -.
DR Reactome; REACT_11123; Membrane Trafficking.
DR Reactome; REACT_116125; Disease.
DR Reactome; REACT_6900; Immune System.
DR GeneWiki; AP1S1; -.
DR GenomeRNAi; 1174; -.
DR NextBio; 4850; -.
DR PRO; PR:P61966; -.
DR Bgee; P61966; -.
DR CleanEx; HS_AP1S1; -.
DR Genevestigator; P61966; -.
DR GO; GO:0030121; C:AP-1 adaptor complex; TAS:UniProtKB.
DR GO; GO:0005905; C:coated pit; IEA:UniProtKB-SubCell.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005765; C:lysosomal membrane; TAS:Reactome.
DR GO; GO:0032588; C:trans-Golgi network membrane; TAS:Reactome.
DR GO; GO:0008565; F:protein transporter activity; IEA:InterPro.
DR GO; GO:0019886; P:antigen processing and presentation of exogenous peptide antigen via MHC class II; TAS:Reactome.
DR GO; GO:0006886; P:intracellular protein transport; IEA:InterPro.
DR GO; GO:0006892; P:post-Golgi vesicle-mediated transport; TAS:Reactome.
DR GO; GO:0006898; P:receptor-mediated endocytosis; TAS:UniProtKB.
DR GO; GO:0050690; P:regulation of defense response to virus by virus; TAS:Reactome.
DR GO; GO:0009615; P:response to virus; IEP:UniProtKB.
DR GO; GO:0016032; P:viral process; TAS:Reactome.
DR InterPro; IPR016635; AP_complex_ssu.
DR InterPro; IPR022775; AP_mu_sigma_su.
DR InterPro; IPR000804; Clathrin_sm-chain_CS.
DR InterPro; IPR011012; Longin-like_dom.
DR PANTHER; PTHR11753; PTHR11753; 1.
DR Pfam; PF01217; Clat_adaptor_s; 1.
DR PIRSF; PIRSF015588; AP_complex_sigma; 1.
DR SUPFAM; SSF64356; SSF64356; 1.
DR PROSITE; PS00989; CLAT_ADAPTOR_S; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Coated pit; Complete proteome;
KW Cytoplasmic vesicle; Deafness; Golgi apparatus; Ichthyosis; Membrane;
KW Mental retardation; Neuropathy; Phosphoprotein; Protein transport;
KW Reference proteome; Transport.
FT CHAIN 1 158 AP-1 complex subunit sigma-1A.
FT /FTId=PRO_0000193797.
FT MOD_RES 147 147 Phosphoserine.
FT VAR_SEQ 128 158 KKSVLKAIEQADLLQEEDESPRSVLEEMGLA -> TFPFSH
FT (in isoform 2).
FT /FTId=VSP_000171.
SQ SEQUENCE 158 AA; 18733 MW; E461937790406D8B CRC64;
MMRFMLLFSR QGKLRLQKWY LATSDKERKK MVRELMQVVL ARKPKMCSFL EWRDLKVVYK
RYASLYFCCA IEGQDNELIT LELIHRYVEL LDKYFGSVCE LDIIFNFEKA YFILDEFLMG
GDVQDTSKKS VLKAIEQADL LQEEDESPRS VLEEMGLA
//

MIM 603531
*RECORD*
*FIELD* NO
603531
*FIELD* TI
*603531 ADAPTOR-RELATED PROTEIN COMPLEX 1, SIGMA-1 SUBUNIT; AP1S1
;;CLATHRIN-ASSOCIATED/ASSEMBLY/ADAPTOR PROTEIN, SMALL 1; CLAPS1;;
read moreCLATHRIN ADAPTOR PROTEIN 19; AP19;;
CLATHRIN ADAPTOR COMPLEX AP1, SIGMA-1A SUBUNIT
*FIELD* TX

DESCRIPTION

The AP1S1 gene encodes the small subunit of the AP-1 complex, which is
involved in protein trafficking by clathrin-coated vesicles. Clathrin
and its associated heterotetrameric protein complexes (APs) are the main
protein components of the coat surrounding the cytoplasmic face of
coated vesicles. Two main types of APs, AP-1 and AP-2, are found in
clathrin-coated structures located at the Golgi complex and the plasma
membrane of mammalian cells, respectively. AP-1 is composed of 2 large
chains, beta-prime-adaptin (600157) and gamma-adaptin (603533); a medium
(mu) chain, AP47 (603535); and a small (sigma) chain, AP19 (summary by
Kirchhausen et al., 1991).

CLONING

Kirchhausen et al. (1991) isolated cDNAs encoding mouse AP19 and rat
AP17 (602242), the small subunit of AP-2. The predicted rat AP17 shares
45% protein sequence identity with mouse AP19. Takatsu et al. (1998)
identified a human cDNA encoding AP19, which they designated sigma-1A.
They reported that the predicted mouse and human AP19 proteins are
identical. Northern blot analysis revealed that the approximately 1.4-kb
AP19 mRNA was expressed ubiquitously in human tissues.

GENE FUNCTION

Doray et al. (2002) demonstrated that the Golgi-localized,
gamma-ear-containing adenosine diphosphate ribosylation factor-binding
proteins (GGA1, 606004 and GGA3, 606006) and the AP-1 complex colocalize
in clathrin-coated buds of the trans-Golgi networks of mouse L cells and
human HeLa cells. Binding studies revealed a direct interaction between
the hinge domains of the GGAs and the gamma-ear domain of AP-1. Further,
AP-1 contained bound casein kinase-2 (see CSNK2A1, 115440) that
phosphorylated GGA1 and GGA3, thereby causing autoinhibition. Doray et
al. (2002) demonstrated that this autoinhibition could induce the
directed transfer of mannose 6-phosphate receptors (see 154540) from the
GGAs to AP-1. Mannose 6-phosphate receptors that were defective in
binding to GGAs were poorly incorporated into adaptor protein complex
containing clathrin coated vesicles. Thus, Doray et al. (2002) concluded
that GGAs and the AP-1 complex interact to package mannose 6-phosphate
receptors into AP-1-containing coated vesicles.

Using a library of endoribonuclease-prepared short interfering RNAs
(esiRNAs), Kittler et al. (2004) identified 37 genes required for cell
division, one of which was AP1S1. These 37 genes included several
splicing factors for which knockdown generates mitotic spindle defects.
In addition, a putative nuclear-export terminator was found to speed up
cell proliferation and mitotic progression after knockdown.

MAPPING

By analysis of a somatic cell hybrid panel, Peyrard et al. (1998) mapped
the AP19 gene to human chromosome 7.

MOLECULAR GENETICS

In affected members of 4 families from Quebec with mental retardation,
enteropathy, deafness, neuropathy, ichthyosis, and keratoderma (MEDNIK;
609313) (Saba et al., 2005), Montpetit et al. (2008) identified a
homozygous splice site mutation in the AP1S1 gene (603531.0001). The
mutation was identified by linkage analysis followed by candidate gene
sequencing. The mutation was predicted to result in a truncated protein
with loss of function, but a small amount of an AP1S1 protein with an
in-frame deletion was also produced, which may have contributed some
residual activity. Knockdown of the Ap1s1 gene in zebrafish resulted in
skin and neurologic defects (see ANIMAL MODEL).

ANIMAL MODEL

Montpetit et al. (2008) found that knockdown of the Ap1s1 gene in
zebrafish caused smaller larvae with reduced pigmentation compared to
wildtype. The larvae had prominent changes in the skin organization with
disorganized fins. Immunolabeling showed abnormal localization of
laminin (see, e.g., 150320) and cadherin (see, e.g., 192090) in the
skin, which was predicted to lead to a loss of epidermal layer
integrity. Knockdown of Ap1s1 in zebrafish also caused severe motor
impairment and impaired spinal cord development with decreased numbers
of interneurons. These defects could be rescued by injection of human
wildtype AP1S1. Knockdown of Ap1s1 was lethal at later embryonic stages.

*FIELD* AV
.0001
MENTAL RETARDATION, ENTEROPATHY, DEAFNESS, PERIPHERAL NEUROPATHY,
ICHTHYOSIS, AND KERATODERMA
AP1S1, IVS2AS, A-G, -2

In affected members of 4 families from Quebec with mental retardation,
enteropathy, deafness, neuropathy, ichthyosis, and keratoderma (MEDNIK;
609313), Montpetit et al. (2008) identified a homozygous A-to-G
transition in intron 2 of the AP1S1 gene, resulting in the skipping of
exon 3 and premature termination, consistent with a loss of function.
RT-PCR analysis of patient fibroblasts showed no full-length AP1S1 mRNA
species, but there was an mRNA isoform predicted to result in a protein
with an in-frame deletion generated by use of a cryptic splice acceptor
site. Patients had less than 10% of the expected amount of mRNA, but the
in-frame deletion protein may have contributed some residual activity.
The mutation was found by linkage analysis followed by candidate gene
sequencing. All unaffected parents were heterozygous for the mutation,
which was not found in 180 controls.

*FIELD* RF
1. Doray, B.; Ghosh, P.; Griffith, J.; Geuze, H. J.; Kornfeld, S.
: Cooperation of GGAs and AP-1 in packaging MPRs at the trans-Golgi
network. Science 297: 1700-1703, 2002.

2. Kirchhausen, T.; Davis, A. C.; Frucht, S.; O'Brine Greco, B.; Payne,
G. S.; Tubb, B.: AP17 and AP19, the mammalian small chains of the
clathrin-associated protein complexes show homology to Yap17p, their
putative homolog in yeast. J. Biol. Chem. 266: 11153-11157, 1991.

3. Kittler, R.; Putz, G.; Pelletier, L.; Poser, I.; Heninger, A.-K.;
Drechsel, D.; Fischer, S.; Konstantinova, I.; Habermann, B.; Grabner,
H.; Yaspo, M.-L.; Himmelbauer, H.; Korn, B.; Neugebauer, K.; Pisabarro,
M. T.; Buchholz, F.: An endoribonuclease-prepared siRNA screen in
human cells identifies genes essential for cell division. Nature 432:
1036-1040, 2004.

4. Montpetit, A.; Cote, S.; Brustein, E.; Drouin, C. A.; Lapointe,
L.; Boudreau, M.; Meloche, C.; Drouin, R.; Hudson, T. J.; Drapeau,
P.; Cossette, P.: Disruption of AP1S1, causing a novel neurocutaneous
syndrome, perturbs development of the skin and spinal cord. PLoS
Genet. 4: e1000296, 2008. Note: Electronic Article.

5. Peyrard, M.; Parveneh, S.; Lagercrantz, S.; Ekman, M.; Fransson,
I.; Sahlen, S.; Dumanski, J. P.: Cloning, expression pattern, and
chromosomal assignment to 16q23 of the human gamma-adaptin gene (ADTG). Genomics 50:
275-280, 1998.

6. Saba, T. G.; Montpetit, A.; Verner, A.; Rioux, P.; Hudson, T. J.;
Drouin, R.; Drouin, C. A.: An atypical form of erythrokeratodermia
variabilis maps to chromosome 7q22. Hum. Genet. 116: 167-171, 2005.

7. Takatsu, H.; Sakurai, M.; Shin, H.-W.; Murakami, K.; Nakayama,
K.: Identification and characterization of novel clathrin adaptor-related
proteins. J. Biol. Chem. 273: 24693-24700, 1998.

*FIELD* CN
Cassandra L. Kniffin - updated: 12/11/2012
Ada Hamosh - updated: 3/8/2005
Ada Hamosh - updated: 10/23/2002

*FIELD* CD
Rebekah S. Rasooly: 2/15/1999

*FIELD* ED
carol: 09/24/2013
carol: 9/19/2013
tpirozzi: 9/19/2013
carol: 8/16/2013
carol: 3/15/2013
carol: 12/14/2012
ckniffin: 12/11/2012
alopez: 3/8/2005
alopez: 10/23/2002
carol: 4/11/2001
alopez: 2/15/1999

MIM 609313
*RECORD*
*FIELD* NO
609313
*FIELD* TI
#609313 MENTAL RETARDATION, ENTEROPATHY, DEAFNESS, PERIPHERAL NEUROPATHY,
ICHTHYOSIS, AND KERATODERMA; MEDNIK
read more;;ERYTHROKERATODERMIA VARIABILIS 3; EKV3;;
ERYTHROKERATODERMIA VARIABILIS, KAMOURASKA TYPE
*FIELD* TX
A number sign (#) is used with this entry because mental retardation,
enteropathy, deafness, peripheral neuropathy, ichthyosis, and
keratoderma (MEDNIK) is caused by homozygous mutation in the AP1S1 gene
(603531) on chromosome 7q22.

DESCRIPTION

MEDNIK is a severe multisystem disorder characterized by mental
retardation, enteropathy, deafness, peripheral neuropathy, ichthyosis,
and keratoderma. It shows phenotypic similarities to CEDNIK (609528)
(summary by Montpetit et al., 2008).

CLINICAL FEATURES

Erythrokeratodermia variabilis (EKV; 133200) is a congenital disorder of
the skin that causes hyperkeratosis and red patches of variable sizes,
shapes, and duration. In 5 children from 3 families originating from the
Kamouraska region of the province of Quebec, Saba et al. (2005)
described an atypical form of erythrokeratodermia variabilis, designated
erythrokeratodermia variabilis-3 (Kamouraska type) and symbolized EKV3.
This form was similar to a disorder previously described by Beare et al.
(1972) and included sensorineural deafness, peripheral neuropathy, and
psychomotor retardation; however, in addition to these symptoms, the
Kamouraska patients had congenital diarrhea, an elevation of very long
chain fatty acids (VLCFAs), and a recessive mode of inheritance. Two of
the children died at an early age from severe congenital diarrhea.

Montpetit et al. (2008) restudied the patients reported by Saba et al.
(2005) and identified another family from Quebec with the disorder.
Features included high forehead with upslanting palpebral fissures,
congenital sensorineural deafness, psychomotor retardation and mental
retardation, peripheral neuropathy, hypotonia, and ichthyosiform
erythroderma. Gastrointestinal problems included severe diarrhea,
resulting in death in infancy in 4 patients, hepatic fibrosis,
cirrhosis, and cholestasis. Two patients had cataracts.

INHERITANCE

The transmission pattern in the families with MEDNIK reported by Saba et
al. (2005) and Montpetit et al. (2008) was consistent with autosomal
recessive inheritance.

MAPPING

By homozygosity mapping, Saba et al. (2005) excluded GJB3 (603324) on
chromosome 1 as a candidate gene for EKV3; the same approach identified
a large region on chromosome 7 that was identical by descent in all
affected individuals but not in an unaffected first-degree relative. The
assignment was narrowed to a 6.8-Mb region of chromosome 7q22 containing
approximately 100 genes, 1 of which was CX31.3 (GJC3; 611925).
Sequencing of the 2 known coding exons of the GJC3 gene revealed no
mutations.

Montpetit et al. (2008) identified another family from Quebec with a
phenotype similar to that described by Saba et al. (2005). Linkage
analysis refined the critical region to 5.3 Mb between D7S2539 and
D7S518.

MOLECULAR GENETICS

In affected members from 4 families with MEDNIK, Montpetit et al. (2008)
identified the same homozygous splice site mutation in the AP1S1 gene
(603531.0001). The mutation was identified by linkage analysis followed
by candidate gene sequencing. The mutation was predicted to result in a
truncated protein with loss of function, but a small amount of an AP1S1
protein with an in-frame deletion was also produced, which may have
contributed some residual activity. Knockdown of the Ap1s1 gene in
zebrafish resulted in skin and neurologic defects. The AP1S1 gene is
involved in protein trafficking between organelles.

POPULATION GENETICS

All 3 families with MEDNIK reported by Saba et al. (2005) were likely to
share common ancestors, as they lived in a relatively isolated
population descended from founders of French origin who settled south of
the St. Lawrence downstream of Quebec City in the 17th and 18th
centuries.

HISTORY

See 606945.0025 for a deletion of the promoter and exon 1 of the LDLR
gene causing a form of familial hypercholesterolemia called French
Canadian-1, which has been identified in individuals living in the
Kamouraska region of the province of Quebec.

*FIELD* RF
1. Beare, J. M.; Nevin, N. C.; Froggatt, P.; Kernohan, D. C.; Allen,
I. V.: Atypical erythrokeratoderma with deafness, physical retardation
and peripheral neuropathy. Brit. J. Derm. 87: 308-314, 1972.

2. Montpetit, A.; Cote, S.; Brustein, E.; Drouin, C. A.; Lapointe,
L.; Boudreau, M.; Meloche, C.; Drouin, R.; Hudson, T. J.; Drapeau,
P.; Cossette, P.: Disruption of AP1S1, causing a novel neurocutaneous
syndrome, perturbs development of the skin and spinal cord. PLoS
Genet. 4: e1000296, 2008. Note: Electronic Article.

3. Saba, T. G.; Montpetit, A.; Verner, A.; Rioux, P.; Hudson, T. J.;
Drouin, R.; Drouin, C. A.: An atypical form of erythrokeratodermia
variabilis maps to chromosome 7q22. Hum. Genet. 116: 167-171, 2005.

*FIELD* CS
INHERITANCE:
Autosomal recessive

GROWTH:
[Other];
Growth retardation

HEAD AND NECK:
[Head];
High forehead;
[Ears];
Deafness, sensorineural, congenital;
[Eyes];
Upslanting palpebral fissures;
Cataracts (uncommon)

ABDOMEN:
[Liver];
Hepatic fibrosis;
Cirrhosis;
Cholestasis;
[Gastrointestinal];
Diarrhea;
Enteropathy

SKIN, NAILS, HAIR:
[Skin];
Erythema;
Ichthyosis

MUSCLE, SOFT TISSUE:
Hypotonia

NEUROLOGIC:
[Central nervous system];
Delayed psychomotor development;
Mental retardation;
Hypotonia;
[Peripheral nervous system];
Peripheral neuropathy

LABORATORY ABNORMALITIES:
Increased very-long chain fatty acids

MISCELLANEOUS:
Onset at birth;
May result in early death from severe diarrhea;
Prevalent in Quebec

MOLECULAR BASIS:
Caused by mutation in the adaptor-related protein complex 1, sigma-1
subunit gene (AP1S1, 603531.0001)

*FIELD* CD
Cassandra L. Kniffin: 12/11/2012

*FIELD* ED
joanna: 06/04/2013
ckniffin: 12/11/2012

*FIELD* CN
Cassandra L. Kniffin - updated: 12/11/2012

*FIELD* CD
Victor A. McKusick: 4/15/2005

*FIELD* ED
tpirozzi: 09/19/2013
carol: 12/14/2012
ckniffin: 12/11/2012
carol: 9/9/2008
carol: 12/26/2007
tkritzer: 4/15/2005