Full text data of AP2S1
AP2S1
(AP17, CLAPS2)
[Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
AP-2 complex subunit sigma (Adapter-related protein complex 2 subunit sigma; Adaptor protein complex AP-2 subunit sigma; Clathrin assembly protein 2 sigma small chain; Clathrin coat assembly protein AP17; Clathrin coat-associated protein AP17; HA2 17 kDa subunit; Plasma membrane adaptor AP-2 17 kDa protein; Sigma2-adaptin)
AP-2 complex subunit sigma (Adapter-related protein complex 2 subunit sigma; Adaptor protein complex AP-2 subunit sigma; Clathrin assembly protein 2 sigma small chain; Clathrin coat assembly protein AP17; Clathrin coat-associated protein AP17; HA2 17 kDa subunit; Plasma membrane adaptor AP-2 17 kDa protein; Sigma2-adaptin)
UniProt
P53680
ID AP2S1_HUMAN Reviewed; 142 AA.
AC P53680; B2R4Z4; O75977; Q6PK67;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
read moreDT 16-AUG-2004, sequence version 2.
DT 22-JAN-2014, entry version 113.
DE RecName: Full=AP-2 complex subunit sigma;
DE AltName: Full=Adapter-related protein complex 2 subunit sigma;
DE AltName: Full=Adaptor protein complex AP-2 subunit sigma;
DE AltName: Full=Clathrin assembly protein 2 sigma small chain;
DE AltName: Full=Clathrin coat assembly protein AP17;
DE AltName: Full=Clathrin coat-associated protein AP17;
DE AltName: Full=HA2 17 kDa subunit;
DE AltName: Full=Plasma membrane adaptor AP-2 17 kDa protein;
DE AltName: Full=Sigma2-adaptin;
GN Name=AP2S1; Synonyms=AP17, CLAPS2;
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).
RC TISSUE=Kidney;
RX PubMed=9040778;
RA Winterpacht A., Endele S., Enklaar T., Fuhry M., Zabel B.;
RT "Human CLAPS2 encoding AP17, a small chain of the clathrin-associated
RT protein complex: cDNA cloning and chromosomal assignment to
RT 19q13.2-->q13.3.";
RL Cytogenet. Cell Genet. 75:132-135(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2).
RX PubMed=9767099; DOI=10.1016/S0378-1119(98)00406-5;
RA Holzmann K., Poeltl A., Sauermann G.;
RT "A novel spliced transcript of human CLAPS2 encoding a protein
RT alternative to clathrin adaptor protein AP17.";
RL Gene 220:39-44(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
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.,
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].
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 [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Uterus;
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 [6]
RP FUNCTION OF THE AP-2 COMPLEX IN CLATHRIN-MEDIATED ENDOCYTOSIS.
RX PubMed=14745134; DOI=10.1247/csf.28.419;
RA Nakatsu F., Ohno H.;
RT "Adaptor protein complexes as the key regulators of protein sorting in
RT the post-Golgi network.";
RL Cell Struct. Funct. 28:419-429(2003).
RN [7]
RP FUNCTION OF THE AP-2 COMPLEX IN CLATHRIN-MEDIATED ENDOCYTOSIS.
RX PubMed=15473838; DOI=10.1146/annurev.cellbio.20.010403.104543;
RA Owen D.J., Collins B.M., Evans P.R.;
RT "Adaptors for clathrin coats: structure and function.";
RL Annu. Rev. Cell Dev. Biol. 20:153-191(2004).
RN [8]
RP FUNCTION OF THE AP-2 COMPLEX IN NON-CLATHRIN-DEPENDENT ENDOCYTOSIS.
RX PubMed=19033387; DOI=10.1242/jcs.033522;
RA Lau A.W., Chou M.M.;
RT "The adaptor complex AP-2 regulates post-endocytic trafficking through
RT the non-clathrin Arf6-dependent endocytic pathway.";
RL J. Cell Sci. 121:4008-4017(2008).
RN [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-140, 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 [10]
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).
RN [11]
RP FUNCTION, VARIANTS HHC3 CYS-15; HIS-15 AND LEU-15, AND
RP CHARACTERIZATION OF VARIANTS HHC3 CYS-15; HIS-15 AND LEU-15.
RX PubMed=23222959; DOI=10.1038/ng.2492;
RA Nesbit M.A., Hannan F.M., Howles S.A., Reed A.A., Cranston T.,
RA Thakker C.E., Gregory L., Rimmer A.J., Rust N., Graham U.,
RA Morrison P.J., Hunter S.J., Whyte M.P., McVean G., Buck D.,
RA Thakker R.V.;
RT "Mutations in AP2S1 cause familial hypocalciuric hypercalcemia type
RT 3.";
RL Nat. Genet. 45:93-97(2013).
CC -!- FUNCTION: Component of the adaptor protein complex 2 (AP-2).
CC Adaptor protein complexes function in protein Transport via
CC Transport vesicles in different membrane traffic pathways. Adaptor
CC protein complexes are vesicle coat components and appear to be
CC involved in cargo selection and vesicle formation. AP-2 is
CC involved in clathrin-dependent endocytosis in which cargo proteins
CC are incorporated into vesicles surrounded by clathrin (clathrin-
CC coated vesicles, CCVs) which are destined for fusion with the
CC early endosome. The clathrin lattice serves as a mechanical
CC scaffold but is itself unable to bind directly to membrane
CC components. Clathrin-associated adaptor protein (AP) complexes
CC which can bind directly to both the clathrin lattice and to the
CC lipid and protein components of membranes are considered to be the
CC major clathrin adaptors contributing the CCV formation. AP-2 also
CC serves as a cargo receptor to selectively sort the membrane
CC proteins involved in receptor-mediated endocytosis. AP-2 seems to
CC play a role in the recycling of synaptic vesicle membranes from
CC the presynaptic surface. AP-2 recognizes Y-X-X-[FILMV] (Y-X-X-Phi)
CC and [ED]-X-X-X-L-[LI] endocytosis signal motifs within the
CC cytosolic tails of transmembrane cargo molecules. AP-2 may also
CC play a role in maintaining normal post-endocytic trafficking
CC through the ARF6-regulated, non-clathrin pathway. The AP-2 alpha
CC and AP-2 sigma subunits are thought to contribute to the
CC recognition of the [ED]-X-X-X-L-[LI] motif (By similarity). May
CC also play a role in extracellular calcium homeostasis.
CC -!- SUBUNIT: Adaptor protein complex 2 (AP-2) is a heterotetramer
CC composed of two large adaptins (alpha-type subunit AP2A1 or AP2A2
CC and beta-type subunit AP2B1), a medium adaptin (mu-type subunit
CC AP2M1) and a small adaptin (sigma-type subunit AP2S1).
CC -!- SUBCELLULAR LOCATION: Cell membrane. Membrane, coated pit;
CC Peripheral membrane protein; Cytoplasmic side. Note=AP-2 appears
CC to be excluded from internalizing CCVs and to disengage from sites
CC of endocytosis seconds before internalization of the nascent CCV
CC (By similarity).
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P53680-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P53680-2; Sequence=VSP_017352;
CC -!- DISEASE: Hypocalciuric hypercalcemia, familial 3 (HHC3)
CC [MIM:600740]: A form of hypocalciuric hypercalcemia, a disorder of
CC mineral homeostasis that is transmitted as an autosomal dominant
CC trait with a high degree of penetrance. It is characterized
CC biochemically by lifelong elevation of serum calcium
CC concentrations and is associated with inappropriately low urinary
CC calcium excretion and a normal or mildly elevated circulating
CC parathyroid hormone level. Hypermagnesemia is typically present.
CC Affected individuals are usually asymptomatic and the disorder is
CC considered benign. However, chondrocalcinosis and pancreatitis
CC occur in some adults. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the adaptor complexes small subunit family.
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DR EMBL; X97074; CAA65782.1; -; mRNA.
DR EMBL; AJ010148; CAA09018.1; -; mRNA.
DR EMBL; AJ010149; CAA09019.1; -; mRNA.
DR EMBL; AK312003; BAG34941.1; -; mRNA.
DR EMBL; CH471126; EAW57448.1; -; Genomic_DNA.
DR EMBL; BC006337; AAH06337.1; -; mRNA.
DR RefSeq; NP_004060.2; NM_004069.3.
DR RefSeq; NP_067586.1; NM_021575.2.
DR UniGene; Hs.119591; -.
DR ProteinModelPortal; P53680; -.
DR SMR; P53680; 1-142.
DR IntAct; P53680; 6.
DR MINT; MINT-256650; -.
DR STRING; 9606.ENSP00000263270; -.
DR BindingDB; P53680; -.
DR PhosphoSite; P53680; -.
DR DMDM; 51338780; -.
DR PaxDb; P53680; -.
DR PRIDE; P53680; -.
DR DNASU; 1175; -.
DR Ensembl; ENST00000263270; ENSP00000263270; ENSG00000042753.
DR Ensembl; ENST00000601649; ENSP00000470898; ENSG00000042753.
DR GeneID; 1175; -.
DR KEGG; hsa:1175; -.
DR UCSC; uc002pft.1; human.
DR CTD; 1175; -.
DR GeneCards; GC19M047341; -.
DR HGNC; HGNC:565; AP2S1.
DR MIM; 600740; phenotype.
DR MIM; 602242; gene.
DR neXtProt; NX_P53680; -.
DR Orphanet; 101050; Familial hypocalciuric hypercalcemia type 3.
DR PharmGKB; PA24856; -.
DR eggNOG; COG5030; -.
DR HOGENOM; HOG000185227; -.
DR HOVERGEN; HBG050517; -.
DR InParanoid; P53680; -.
DR KO; K11827; -.
DR OrthoDB; EOG7S7SGC; -.
DR PhylomeDB; P53680; -.
DR Reactome; REACT_111045; Developmental Biology.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_116125; Disease.
DR Reactome; REACT_13685; Neuronal System.
DR Reactome; REACT_6900; Immune System.
DR ChiTaRS; AP2S1; human.
DR GeneWiki; AP2S1; -.
DR GenomeRNAi; 1175; -.
DR NextBio; 4856; -.
DR PRO; PR:P53680; -.
DR ArrayExpress; P53680; -.
DR Bgee; P53680; -.
DR CleanEx; HS_AP2S1; -.
DR Genevestigator; P53680; -.
DR GO; GO:0030122; C:AP-2 adaptor complex; TAS:UniProtKB.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0008565; F:protein transporter activity; NAS:UniProtKB.
DR GO; GO:0019886; P:antigen processing and presentation of exogenous peptide antigen via MHC class II; TAS:Reactome.
DR GO; GO:0007411; P:axon guidance; TAS:Reactome.
DR GO; GO:0048268; P:clathrin coat assembly; TAS:UniProtKB.
DR GO; GO:0006897; P:endocytosis; IEA:UniProtKB-KW.
DR GO; GO:0007173; P:epidermal growth factor receptor signaling pathway; TAS:Reactome.
DR GO; GO:0006886; P:intracellular protein transport; IEA:InterPro.
DR GO; GO:0042059; P:negative regulation of epidermal growth factor receptor signaling pathway; TAS:Reactome.
DR GO; GO:0048011; P:neurotrophin TRK receptor signaling pathway; TAS:Reactome.
DR GO; GO:0050690; P:regulation of defense response to virus by virus; TAS:Reactome.
DR GO; GO:0030100; P:regulation of endocytosis; TAS:UniProtKB.
DR GO; GO:0007268; P:synaptic transmission; TAS:Reactome.
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; Cell membrane; Coated pit; Complete proteome;
KW Disease mutation; Endocytosis; Membrane; Phosphoprotein;
KW Protein transport; Reference proteome; Transport.
FT CHAIN 1 142 AP-2 complex subunit sigma.
FT /FTId=PRO_0000193804.
FT MOD_RES 140 140 Phosphoserine.
FT VAR_SEQ 52 89 Missing (in isoform 2).
FT /FTId=VSP_017352.
FT VARIANT 15 15 R -> C (in HHC3; there is a rightward
FT shift in Ca(2+)concentration-response
FT curves with the mutant compared to wild-
FT type, indicating a decrease in the
FT sensitivity of cells expressing CASR to
FT extracellular calcium).
FT /FTId=VAR_069570.
FT VARIANT 15 15 R -> H (in HHC3; there is a rightward
FT shift in Ca(2+)concentration-response
FT curves with the mutant compared to wild-
FT type, indicating a decrease in the
FT sensitivity of cells expressing CASR to
FT extracellular calcium).
FT /FTId=VAR_069571.
FT VARIANT 15 15 R -> L (in HHC3; there is a rightward
FT shift in Ca(2+)concentration-response
FT curves with the mutant compared to wild-
FT type, indicating a decrease in the
FT sensitivity of cells expressing CASR to
FT extracellular calcium).
FT /FTId=VAR_069572.
FT CONFLICT 77 77 N -> K (in Ref. 1; CAA65782 and 2;
FT CAA09018).
FT CONFLICT 83 83 A -> G (in Ref. 1; CAA65782 and 2;
FT CAA09018).
SQ SEQUENCE 142 AA; 17018 MW; CA3FD868C65AEDF6 CRC64;
MIRFILIQNR AGKTRLAKWY MQFDDDEKQK LIEEVHAVVT VRDAKHTNFV EFRNFKIIYR
RYAGLYFCIC VDVNDNNLAY LEAIHNFVEV LNEYFHNVCE LDLVFNFYKV YTVVDEMFLA
GEIRETSQTK VLKQLLMLQS LE
//
ID AP2S1_HUMAN Reviewed; 142 AA.
AC P53680; B2R4Z4; O75977; Q6PK67;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
read moreDT 16-AUG-2004, sequence version 2.
DT 22-JAN-2014, entry version 113.
DE RecName: Full=AP-2 complex subunit sigma;
DE AltName: Full=Adapter-related protein complex 2 subunit sigma;
DE AltName: Full=Adaptor protein complex AP-2 subunit sigma;
DE AltName: Full=Clathrin assembly protein 2 sigma small chain;
DE AltName: Full=Clathrin coat assembly protein AP17;
DE AltName: Full=Clathrin coat-associated protein AP17;
DE AltName: Full=HA2 17 kDa subunit;
DE AltName: Full=Plasma membrane adaptor AP-2 17 kDa protein;
DE AltName: Full=Sigma2-adaptin;
GN Name=AP2S1; Synonyms=AP17, CLAPS2;
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).
RC TISSUE=Kidney;
RX PubMed=9040778;
RA Winterpacht A., Endele S., Enklaar T., Fuhry M., Zabel B.;
RT "Human CLAPS2 encoding AP17, a small chain of the clathrin-associated
RT protein complex: cDNA cloning and chromosomal assignment to
RT 19q13.2-->q13.3.";
RL Cytogenet. Cell Genet. 75:132-135(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2).
RX PubMed=9767099; DOI=10.1016/S0378-1119(98)00406-5;
RA Holzmann K., Poeltl A., Sauermann G.;
RT "A novel spliced transcript of human CLAPS2 encoding a protein
RT alternative to clathrin adaptor protein AP17.";
RL Gene 220:39-44(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
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.,
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].
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 [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Uterus;
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 [6]
RP FUNCTION OF THE AP-2 COMPLEX IN CLATHRIN-MEDIATED ENDOCYTOSIS.
RX PubMed=14745134; DOI=10.1247/csf.28.419;
RA Nakatsu F., Ohno H.;
RT "Adaptor protein complexes as the key regulators of protein sorting in
RT the post-Golgi network.";
RL Cell Struct. Funct. 28:419-429(2003).
RN [7]
RP FUNCTION OF THE AP-2 COMPLEX IN CLATHRIN-MEDIATED ENDOCYTOSIS.
RX PubMed=15473838; DOI=10.1146/annurev.cellbio.20.010403.104543;
RA Owen D.J., Collins B.M., Evans P.R.;
RT "Adaptors for clathrin coats: structure and function.";
RL Annu. Rev. Cell Dev. Biol. 20:153-191(2004).
RN [8]
RP FUNCTION OF THE AP-2 COMPLEX IN NON-CLATHRIN-DEPENDENT ENDOCYTOSIS.
RX PubMed=19033387; DOI=10.1242/jcs.033522;
RA Lau A.W., Chou M.M.;
RT "The adaptor complex AP-2 regulates post-endocytic trafficking through
RT the non-clathrin Arf6-dependent endocytic pathway.";
RL J. Cell Sci. 121:4008-4017(2008).
RN [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-140, 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 [10]
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).
RN [11]
RP FUNCTION, VARIANTS HHC3 CYS-15; HIS-15 AND LEU-15, AND
RP CHARACTERIZATION OF VARIANTS HHC3 CYS-15; HIS-15 AND LEU-15.
RX PubMed=23222959; DOI=10.1038/ng.2492;
RA Nesbit M.A., Hannan F.M., Howles S.A., Reed A.A., Cranston T.,
RA Thakker C.E., Gregory L., Rimmer A.J., Rust N., Graham U.,
RA Morrison P.J., Hunter S.J., Whyte M.P., McVean G., Buck D.,
RA Thakker R.V.;
RT "Mutations in AP2S1 cause familial hypocalciuric hypercalcemia type
RT 3.";
RL Nat. Genet. 45:93-97(2013).
CC -!- FUNCTION: Component of the adaptor protein complex 2 (AP-2).
CC Adaptor protein complexes function in protein Transport via
CC Transport vesicles in different membrane traffic pathways. Adaptor
CC protein complexes are vesicle coat components and appear to be
CC involved in cargo selection and vesicle formation. AP-2 is
CC involved in clathrin-dependent endocytosis in which cargo proteins
CC are incorporated into vesicles surrounded by clathrin (clathrin-
CC coated vesicles, CCVs) which are destined for fusion with the
CC early endosome. The clathrin lattice serves as a mechanical
CC scaffold but is itself unable to bind directly to membrane
CC components. Clathrin-associated adaptor protein (AP) complexes
CC which can bind directly to both the clathrin lattice and to the
CC lipid and protein components of membranes are considered to be the
CC major clathrin adaptors contributing the CCV formation. AP-2 also
CC serves as a cargo receptor to selectively sort the membrane
CC proteins involved in receptor-mediated endocytosis. AP-2 seems to
CC play a role in the recycling of synaptic vesicle membranes from
CC the presynaptic surface. AP-2 recognizes Y-X-X-[FILMV] (Y-X-X-Phi)
CC and [ED]-X-X-X-L-[LI] endocytosis signal motifs within the
CC cytosolic tails of transmembrane cargo molecules. AP-2 may also
CC play a role in maintaining normal post-endocytic trafficking
CC through the ARF6-regulated, non-clathrin pathway. The AP-2 alpha
CC and AP-2 sigma subunits are thought to contribute to the
CC recognition of the [ED]-X-X-X-L-[LI] motif (By similarity). May
CC also play a role in extracellular calcium homeostasis.
CC -!- SUBUNIT: Adaptor protein complex 2 (AP-2) is a heterotetramer
CC composed of two large adaptins (alpha-type subunit AP2A1 or AP2A2
CC and beta-type subunit AP2B1), a medium adaptin (mu-type subunit
CC AP2M1) and a small adaptin (sigma-type subunit AP2S1).
CC -!- SUBCELLULAR LOCATION: Cell membrane. Membrane, coated pit;
CC Peripheral membrane protein; Cytoplasmic side. Note=AP-2 appears
CC to be excluded from internalizing CCVs and to disengage from sites
CC of endocytosis seconds before internalization of the nascent CCV
CC (By similarity).
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P53680-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P53680-2; Sequence=VSP_017352;
CC -!- DISEASE: Hypocalciuric hypercalcemia, familial 3 (HHC3)
CC [MIM:600740]: A form of hypocalciuric hypercalcemia, a disorder of
CC mineral homeostasis that is transmitted as an autosomal dominant
CC trait with a high degree of penetrance. It is characterized
CC biochemically by lifelong elevation of serum calcium
CC concentrations and is associated with inappropriately low urinary
CC calcium excretion and a normal or mildly elevated circulating
CC parathyroid hormone level. Hypermagnesemia is typically present.
CC Affected individuals are usually asymptomatic and the disorder is
CC considered benign. However, chondrocalcinosis and pancreatitis
CC occur in some adults. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the adaptor complexes small subunit family.
CC -----------------------------------------------------------------------
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CC Distributed under the Creative Commons Attribution-NoDerivs License
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DR EMBL; X97074; CAA65782.1; -; mRNA.
DR EMBL; AJ010148; CAA09018.1; -; mRNA.
DR EMBL; AJ010149; CAA09019.1; -; mRNA.
DR EMBL; AK312003; BAG34941.1; -; mRNA.
DR EMBL; CH471126; EAW57448.1; -; Genomic_DNA.
DR EMBL; BC006337; AAH06337.1; -; mRNA.
DR RefSeq; NP_004060.2; NM_004069.3.
DR RefSeq; NP_067586.1; NM_021575.2.
DR UniGene; Hs.119591; -.
DR ProteinModelPortal; P53680; -.
DR SMR; P53680; 1-142.
DR IntAct; P53680; 6.
DR MINT; MINT-256650; -.
DR STRING; 9606.ENSP00000263270; -.
DR BindingDB; P53680; -.
DR PhosphoSite; P53680; -.
DR DMDM; 51338780; -.
DR PaxDb; P53680; -.
DR PRIDE; P53680; -.
DR DNASU; 1175; -.
DR Ensembl; ENST00000263270; ENSP00000263270; ENSG00000042753.
DR Ensembl; ENST00000601649; ENSP00000470898; ENSG00000042753.
DR GeneID; 1175; -.
DR KEGG; hsa:1175; -.
DR UCSC; uc002pft.1; human.
DR CTD; 1175; -.
DR GeneCards; GC19M047341; -.
DR HGNC; HGNC:565; AP2S1.
DR MIM; 600740; phenotype.
DR MIM; 602242; gene.
DR neXtProt; NX_P53680; -.
DR Orphanet; 101050; Familial hypocalciuric hypercalcemia type 3.
DR PharmGKB; PA24856; -.
DR eggNOG; COG5030; -.
DR HOGENOM; HOG000185227; -.
DR HOVERGEN; HBG050517; -.
DR InParanoid; P53680; -.
DR KO; K11827; -.
DR OrthoDB; EOG7S7SGC; -.
DR PhylomeDB; P53680; -.
DR Reactome; REACT_111045; Developmental Biology.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_116125; Disease.
DR Reactome; REACT_13685; Neuronal System.
DR Reactome; REACT_6900; Immune System.
DR ChiTaRS; AP2S1; human.
DR GeneWiki; AP2S1; -.
DR GenomeRNAi; 1175; -.
DR NextBio; 4856; -.
DR PRO; PR:P53680; -.
DR ArrayExpress; P53680; -.
DR Bgee; P53680; -.
DR CleanEx; HS_AP2S1; -.
DR Genevestigator; P53680; -.
DR GO; GO:0030122; C:AP-2 adaptor complex; TAS:UniProtKB.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0008565; F:protein transporter activity; NAS:UniProtKB.
DR GO; GO:0019886; P:antigen processing and presentation of exogenous peptide antigen via MHC class II; TAS:Reactome.
DR GO; GO:0007411; P:axon guidance; TAS:Reactome.
DR GO; GO:0048268; P:clathrin coat assembly; TAS:UniProtKB.
DR GO; GO:0006897; P:endocytosis; IEA:UniProtKB-KW.
DR GO; GO:0007173; P:epidermal growth factor receptor signaling pathway; TAS:Reactome.
DR GO; GO:0006886; P:intracellular protein transport; IEA:InterPro.
DR GO; GO:0042059; P:negative regulation of epidermal growth factor receptor signaling pathway; TAS:Reactome.
DR GO; GO:0048011; P:neurotrophin TRK receptor signaling pathway; TAS:Reactome.
DR GO; GO:0050690; P:regulation of defense response to virus by virus; TAS:Reactome.
DR GO; GO:0030100; P:regulation of endocytosis; TAS:UniProtKB.
DR GO; GO:0007268; P:synaptic transmission; TAS:Reactome.
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; Cell membrane; Coated pit; Complete proteome;
KW Disease mutation; Endocytosis; Membrane; Phosphoprotein;
KW Protein transport; Reference proteome; Transport.
FT CHAIN 1 142 AP-2 complex subunit sigma.
FT /FTId=PRO_0000193804.
FT MOD_RES 140 140 Phosphoserine.
FT VAR_SEQ 52 89 Missing (in isoform 2).
FT /FTId=VSP_017352.
FT VARIANT 15 15 R -> C (in HHC3; there is a rightward
FT shift in Ca(2+)concentration-response
FT curves with the mutant compared to wild-
FT type, indicating a decrease in the
FT sensitivity of cells expressing CASR to
FT extracellular calcium).
FT /FTId=VAR_069570.
FT VARIANT 15 15 R -> H (in HHC3; there is a rightward
FT shift in Ca(2+)concentration-response
FT curves with the mutant compared to wild-
FT type, indicating a decrease in the
FT sensitivity of cells expressing CASR to
FT extracellular calcium).
FT /FTId=VAR_069571.
FT VARIANT 15 15 R -> L (in HHC3; there is a rightward
FT shift in Ca(2+)concentration-response
FT curves with the mutant compared to wild-
FT type, indicating a decrease in the
FT sensitivity of cells expressing CASR to
FT extracellular calcium).
FT /FTId=VAR_069572.
FT CONFLICT 77 77 N -> K (in Ref. 1; CAA65782 and 2;
FT CAA09018).
FT CONFLICT 83 83 A -> G (in Ref. 1; CAA65782 and 2;
FT CAA09018).
SQ SEQUENCE 142 AA; 17018 MW; CA3FD868C65AEDF6 CRC64;
MIRFILIQNR AGKTRLAKWY MQFDDDEKQK LIEEVHAVVT VRDAKHTNFV EFRNFKIIYR
RYAGLYFCIC VDVNDNNLAY LEAIHNFVEV LNEYFHNVCE LDLVFNFYKV YTVVDEMFLA
GEIRETSQTK VLKQLLMLQS LE
//
MIM
600740
*RECORD*
*FIELD* NO
600740
*FIELD* TI
#600740 HYPOCALCIURIC HYPERCALCEMIA, FAMILIAL, TYPE III; HHC3
;;FAMILIAL BENIGN HYPERCALCEMIA, TYPE III; FBH3;;
read moreHYPERCALCEMIA, FAMILIAL BENIGN, TYPE III;;
HYPERCALCEMIA, FAMILIAL BENIGN, OKLAHOMA TYPE
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
familial hypocalciuric hypercalcemia type III (HHC3) is caused by
heterozygous mutation in the AP2S1 gene (602242) on chromosome 19q13.
For a general phenotypic description and discussion of genetic
heterogeneity of hypocalciuric hypercalcemia, see HCC1 (145980).
CLINICAL FEATURES
McMurtry et al. (1992) provided clinical and metabolic characterization
of familial hypocalciuric hypercalcemia in a kindred from Oklahoma.
Nineteen affected members were found. Immunoreactive parathyroid hormone
(iPTH) levels, determined in 3 separate immunoassays, became supranormal
by about age 30 years in the group of 15 hypercalcemic subjects examined
biochemically and appeared to increase further thereafter. Serum
alkaline phosphatase activity and creatinine levels were normal in these
individuals, but inorganic phosphate levels were lower than in
unaffected members of the kindred. Three of 5 affected adults older than
age 40 years who were studied radiographically had changes suggestive of
osteomalacia. Biopsy of the iliac crest in one of these subjects, a
51-year-old woman, confirmed the presence of defective skeletal
mineralization. Differentiation from primary hyperparathyroidism was
especially difficult in this kindred because serum iPTH levels may be
elevated. Furthermore, the disorder may not be totally benign.
Osteomalacia, perhaps due to mild hypophosphatemia, can develop during
adulthood in these patients.
Nesbit et al. (2010) studied a kindred from Northern Ireland in which 16
individuals over 3 generations had hypocalciuric hypercalcemia in
association with normal or elevated PTH concentrations. In addition, the
16 individuals had significantly higher serum magnesium and PTH levels
than their normocalcemic relatives, and hypercalcemic individuals above
the age of 30 years had a significantly lower serum phosphate
concentration than those below the age of 30 years. Nesbit et al. (2010)
noted that these features were all consistent with HHC3, although unlike
the Oklahoma family originally described by McMurtry et al. (1992), the
Northern Ireland kindred did not exhibit developmental elevations in
serum PTH concentration or hypophosphatemic osteomalacia in older
affected members.
MAPPING
Trump et al. (1995) studied a 5-generation kindred from Oklahoma,
originally reported by McMurtry et al. (1992), in which there were 19
individuals with hypocalciuric hypercalcemia and 2 obligate carriers.
Trump et al. (1995) demonstrated lack of linkage to the sites of
familial benign hypocalciuric hypercalcemia (HCC1) on 3q21-q24 (145980;
see also 601199) and 19p13.3 (HHC2; 145981), as well as lack of linkage
to 11q13 and 11p15, where the genes for multiple endocrine neoplasia
type I (MEN1; 131100) and PTH (168450) have been mapped, respectively.
Thus, this form of FHH, designated the Oklahoma variant, represents a
distinct genetic entity.
Lloyd et al. (1999) established linkage between the Oklahoma form of
familial benign hypercalcemia and 8 loci in the 19q13 region, with the
highest lod score, 6.67 (recombination fraction = 0.00), obtained with
D19S606. Recombination events narrowed the critical region to an
approximately 12-cM interval flanked by D19S908 and D19S866.
In the Oklahoma kindred with hypocalciuric hypercalcemia that was
originally described by McMurtry et al. (1992), Hannan et al. (2010)
used 24 polymorphic loci to refine further the HHC3 locus to a 4.1-Mb
region flanked by D19S112 and SNP dbSNP rs245111.
In a 3-generation kindred from Northern Ireland with hypocalciuric
hypercalcemia, in which mutation in the CASR gene (601199) and linkage
to the CASR locus had been excluded, Nesbit et al. (2010) analyzed 11
polymorphic loci on chromosome 19q13 and established linkage between HHC
and 8 of the loci, obtaining the highest peak lod score of 5.98 at
D19S412 (theta = 0). Haplotype analysis indicated that the Oklahoma
kindred with HHC mapping to chromosome 19q13, originally studied by
McMurtry et al. (1992), and the Northern Ireland kindred were not
related. Recombination events in the Northern Ireland family narrowed
the critical region to a 3.46-Mb interval flanked centromerically by
dbSNP rs1990932 and telomerically by D19S604; combining these data with
those of the Oklahoma kindred defined a 2.79-Mb minimum nonrecombinant
interval flanked by dbSNP rs1019212 and D19S879.
MOLECULAR GENETICS
Using exome capture and high-throughput sequence analysis of genomic DNA
from an affected individual from each of 2 unrelated kindreds with HHC
mapping to chromosome 19q13, originally described by McMurtry et al.
(1992) and Nesbit et al. (2010), respectively, Nesbit et al. (2013)
identified a heterozygous missense mutation in the AP2S1 gene (R15C;
602242.0001). The mutation, which was confirmed by dideoxynucleotide
sequencing, segregated completely with disease in each family and was
not found in 55 normocalcemic controls. Analysis of the AP2S1 gene in 50
unrelated patients with HHC who were negative for mutation in the CASR
gene identified 11 who were heterozygous for AP2S1 missense mutations,
all of which involved the R15 residue: R15C in 4 patients, R15L
(602242.0002) in 4 patients, and R15H (602242.0003) in 3 patients.
- Exclusion Studies
In an affected individual from an Oklahoma kindred with hypocalciuric
hypercalcemia mapping to chromosome 19q13, originally reported by
McMurtry et al. (1992), Hannan et al. (2010) analyzed 12 candidate genes
but found no abnormalities.
*FIELD* RF
1. Hannan, F. M.; Nesbit, M. A.; Turner, J. J. O.; Stacey, J. M.;
Cianferotti, L.; Christie, P. T.; Conigrave, A. D.; Whyte, M. P.;
Thakker, R. V.: Comparison of human chromosome 19q13 and syntenic
region on mouse chromosome 7 reveals absence, in man, of 11.6 Mb containing
four mouse calcium-sensing receptor-related sequences: relevance to
familial benign hypocalciuric hypercalcaemia type 3. Europ. J. Hum.
Genet. 18: 442-447, 2010.
2. Lloyd, S. E.; Pannett, A. A. J.; Dixon, P. H.; Whyte, M. P.; Thakker,
R. V.: Localization of familial benign hypercalcemia, Oklahoma variant
(FBH-Ok), to chromosome 19q13. Am. J. Hum. Genet. 64: 189-195, 1999.
3. McMurtry, C. T.; Schranck, F. W.; Walkenhorst, D. A.; Murphy, W.
A.; Kocher, D. B.; Teitelbaum, S. L.; Rupich, R. C.; Whyte, M. P.
: Significant developmental elevation in serum parathyroid hormone
levels in a large kindred with familial benign (hypocalciuric) hypercalcemia. Am.
J. Med. 93: 247-258, 1992.
4. Nesbit, M. A.; Hannan, F. M.; Graham, U.; Whyte, M. P.; Morrison,
P. J.; Hunter, S. J.; Thakker, R. V.: Identification of a second
kindred with familial hypocalciuric hypercalcemia type 3 (FHH3) narrows
localization to a less than 3.5 megabase pair region on chromosome
19q13.3. J. Clin. Endocrin. Metab. 95: 1947-1954, 2010.
5. Nesbit, M. A.; Hannan, F. M.; Howles, S. A.; Reed, A. A. C.; Cranston,
T.; Thakker, C. E.; Gregory, L.; Rimmer, A. J.; Rust, N.; Graham,
U.; Morrison, P. J.; Hunter, S. J.; Whyte, M. P.; McVean, G.; Buck,
D.; Thakker, R. V.: Mutations in AP2S1 cause familial hypocalciuric
hypercalcemia type 3. Nature Genet. 45: 93-97, 2013.
6. Trump, D.; Whyte, M. P.; Wooding, C.; Pang, J. T.; Pearce, S. H.
S.; Kocher, D. B.; Thakker, R. V.: Linkage studies in a kindred from
Oklahoma, with familial benign (hypocalciuric) hypercalcaemia (FBH)
and developmental elevations in serum parathyroid hormone levels,
indicate a third locus for FBH. Hum. Genet. 96: 183-187, 1995.
*FIELD* CS
GU:
Nephrolithiasis uncommon
GI:
Peptic ulcer uncommon;
Pancreatitis
Skin:
Lipomas
Misc:
Neonatal severe primary hyperparathyroidism in homozygotes
Radiology:
Chondrocalcinosis
Lab:
Hypocalciuria;
Hypercalcemia;
Hypermagnesemia;
Parathormone-independent renal tubular calcium reabsorption defect;
Ratio of renal calcium clearance to creatinine clearance usually below
0.01
Inheritance:
Autosomal dominant form not linked to either 19p13.3 or 3q21-q24
*FIELD* CN
Marla J. F. O'Neill - updated: 2/8/2013
Marla J. F. O'Neill - updated: 11/30/2011
Victor A. McKusick - updated: 2/8/1999
Victor A. McKusick - updated: 10/16/1998
*FIELD* CD
Victor A. McKusick: 8/22/1995
*FIELD* ED
carol: 09/16/2013
carol: 2/8/2013
terry: 2/8/2013
carol: 11/30/2011
joanna: 3/18/2004
carol: 9/17/2003
carol: 2/14/1999
terry: 2/8/1999
terry: 10/16/1998
mark: 4/19/1996
mimadm: 11/3/1995
mark: 8/22/1995
*RECORD*
*FIELD* NO
600740
*FIELD* TI
#600740 HYPOCALCIURIC HYPERCALCEMIA, FAMILIAL, TYPE III; HHC3
;;FAMILIAL BENIGN HYPERCALCEMIA, TYPE III; FBH3;;
read moreHYPERCALCEMIA, FAMILIAL BENIGN, TYPE III;;
HYPERCALCEMIA, FAMILIAL BENIGN, OKLAHOMA TYPE
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
familial hypocalciuric hypercalcemia type III (HHC3) is caused by
heterozygous mutation in the AP2S1 gene (602242) on chromosome 19q13.
For a general phenotypic description and discussion of genetic
heterogeneity of hypocalciuric hypercalcemia, see HCC1 (145980).
CLINICAL FEATURES
McMurtry et al. (1992) provided clinical and metabolic characterization
of familial hypocalciuric hypercalcemia in a kindred from Oklahoma.
Nineteen affected members were found. Immunoreactive parathyroid hormone
(iPTH) levels, determined in 3 separate immunoassays, became supranormal
by about age 30 years in the group of 15 hypercalcemic subjects examined
biochemically and appeared to increase further thereafter. Serum
alkaline phosphatase activity and creatinine levels were normal in these
individuals, but inorganic phosphate levels were lower than in
unaffected members of the kindred. Three of 5 affected adults older than
age 40 years who were studied radiographically had changes suggestive of
osteomalacia. Biopsy of the iliac crest in one of these subjects, a
51-year-old woman, confirmed the presence of defective skeletal
mineralization. Differentiation from primary hyperparathyroidism was
especially difficult in this kindred because serum iPTH levels may be
elevated. Furthermore, the disorder may not be totally benign.
Osteomalacia, perhaps due to mild hypophosphatemia, can develop during
adulthood in these patients.
Nesbit et al. (2010) studied a kindred from Northern Ireland in which 16
individuals over 3 generations had hypocalciuric hypercalcemia in
association with normal or elevated PTH concentrations. In addition, the
16 individuals had significantly higher serum magnesium and PTH levels
than their normocalcemic relatives, and hypercalcemic individuals above
the age of 30 years had a significantly lower serum phosphate
concentration than those below the age of 30 years. Nesbit et al. (2010)
noted that these features were all consistent with HHC3, although unlike
the Oklahoma family originally described by McMurtry et al. (1992), the
Northern Ireland kindred did not exhibit developmental elevations in
serum PTH concentration or hypophosphatemic osteomalacia in older
affected members.
MAPPING
Trump et al. (1995) studied a 5-generation kindred from Oklahoma,
originally reported by McMurtry et al. (1992), in which there were 19
individuals with hypocalciuric hypercalcemia and 2 obligate carriers.
Trump et al. (1995) demonstrated lack of linkage to the sites of
familial benign hypocalciuric hypercalcemia (HCC1) on 3q21-q24 (145980;
see also 601199) and 19p13.3 (HHC2; 145981), as well as lack of linkage
to 11q13 and 11p15, where the genes for multiple endocrine neoplasia
type I (MEN1; 131100) and PTH (168450) have been mapped, respectively.
Thus, this form of FHH, designated the Oklahoma variant, represents a
distinct genetic entity.
Lloyd et al. (1999) established linkage between the Oklahoma form of
familial benign hypercalcemia and 8 loci in the 19q13 region, with the
highest lod score, 6.67 (recombination fraction = 0.00), obtained with
D19S606. Recombination events narrowed the critical region to an
approximately 12-cM interval flanked by D19S908 and D19S866.
In the Oklahoma kindred with hypocalciuric hypercalcemia that was
originally described by McMurtry et al. (1992), Hannan et al. (2010)
used 24 polymorphic loci to refine further the HHC3 locus to a 4.1-Mb
region flanked by D19S112 and SNP dbSNP rs245111.
In a 3-generation kindred from Northern Ireland with hypocalciuric
hypercalcemia, in which mutation in the CASR gene (601199) and linkage
to the CASR locus had been excluded, Nesbit et al. (2010) analyzed 11
polymorphic loci on chromosome 19q13 and established linkage between HHC
and 8 of the loci, obtaining the highest peak lod score of 5.98 at
D19S412 (theta = 0). Haplotype analysis indicated that the Oklahoma
kindred with HHC mapping to chromosome 19q13, originally studied by
McMurtry et al. (1992), and the Northern Ireland kindred were not
related. Recombination events in the Northern Ireland family narrowed
the critical region to a 3.46-Mb interval flanked centromerically by
dbSNP rs1990932 and telomerically by D19S604; combining these data with
those of the Oklahoma kindred defined a 2.79-Mb minimum nonrecombinant
interval flanked by dbSNP rs1019212 and D19S879.
MOLECULAR GENETICS
Using exome capture and high-throughput sequence analysis of genomic DNA
from an affected individual from each of 2 unrelated kindreds with HHC
mapping to chromosome 19q13, originally described by McMurtry et al.
(1992) and Nesbit et al. (2010), respectively, Nesbit et al. (2013)
identified a heterozygous missense mutation in the AP2S1 gene (R15C;
602242.0001). The mutation, which was confirmed by dideoxynucleotide
sequencing, segregated completely with disease in each family and was
not found in 55 normocalcemic controls. Analysis of the AP2S1 gene in 50
unrelated patients with HHC who were negative for mutation in the CASR
gene identified 11 who were heterozygous for AP2S1 missense mutations,
all of which involved the R15 residue: R15C in 4 patients, R15L
(602242.0002) in 4 patients, and R15H (602242.0003) in 3 patients.
- Exclusion Studies
In an affected individual from an Oklahoma kindred with hypocalciuric
hypercalcemia mapping to chromosome 19q13, originally reported by
McMurtry et al. (1992), Hannan et al. (2010) analyzed 12 candidate genes
but found no abnormalities.
*FIELD* RF
1. Hannan, F. M.; Nesbit, M. A.; Turner, J. J. O.; Stacey, J. M.;
Cianferotti, L.; Christie, P. T.; Conigrave, A. D.; Whyte, M. P.;
Thakker, R. V.: Comparison of human chromosome 19q13 and syntenic
region on mouse chromosome 7 reveals absence, in man, of 11.6 Mb containing
four mouse calcium-sensing receptor-related sequences: relevance to
familial benign hypocalciuric hypercalcaemia type 3. Europ. J. Hum.
Genet. 18: 442-447, 2010.
2. Lloyd, S. E.; Pannett, A. A. J.; Dixon, P. H.; Whyte, M. P.; Thakker,
R. V.: Localization of familial benign hypercalcemia, Oklahoma variant
(FBH-Ok), to chromosome 19q13. Am. J. Hum. Genet. 64: 189-195, 1999.
3. McMurtry, C. T.; Schranck, F. W.; Walkenhorst, D. A.; Murphy, W.
A.; Kocher, D. B.; Teitelbaum, S. L.; Rupich, R. C.; Whyte, M. P.
: Significant developmental elevation in serum parathyroid hormone
levels in a large kindred with familial benign (hypocalciuric) hypercalcemia. Am.
J. Med. 93: 247-258, 1992.
4. Nesbit, M. A.; Hannan, F. M.; Graham, U.; Whyte, M. P.; Morrison,
P. J.; Hunter, S. J.; Thakker, R. V.: Identification of a second
kindred with familial hypocalciuric hypercalcemia type 3 (FHH3) narrows
localization to a less than 3.5 megabase pair region on chromosome
19q13.3. J. Clin. Endocrin. Metab. 95: 1947-1954, 2010.
5. Nesbit, M. A.; Hannan, F. M.; Howles, S. A.; Reed, A. A. C.; Cranston,
T.; Thakker, C. E.; Gregory, L.; Rimmer, A. J.; Rust, N.; Graham,
U.; Morrison, P. J.; Hunter, S. J.; Whyte, M. P.; McVean, G.; Buck,
D.; Thakker, R. V.: Mutations in AP2S1 cause familial hypocalciuric
hypercalcemia type 3. Nature Genet. 45: 93-97, 2013.
6. Trump, D.; Whyte, M. P.; Wooding, C.; Pang, J. T.; Pearce, S. H.
S.; Kocher, D. B.; Thakker, R. V.: Linkage studies in a kindred from
Oklahoma, with familial benign (hypocalciuric) hypercalcaemia (FBH)
and developmental elevations in serum parathyroid hormone levels,
indicate a third locus for FBH. Hum. Genet. 96: 183-187, 1995.
*FIELD* CS
GU:
Nephrolithiasis uncommon
GI:
Peptic ulcer uncommon;
Pancreatitis
Skin:
Lipomas
Misc:
Neonatal severe primary hyperparathyroidism in homozygotes
Radiology:
Chondrocalcinosis
Lab:
Hypocalciuria;
Hypercalcemia;
Hypermagnesemia;
Parathormone-independent renal tubular calcium reabsorption defect;
Ratio of renal calcium clearance to creatinine clearance usually below
0.01
Inheritance:
Autosomal dominant form not linked to either 19p13.3 or 3q21-q24
*FIELD* CN
Marla J. F. O'Neill - updated: 2/8/2013
Marla J. F. O'Neill - updated: 11/30/2011
Victor A. McKusick - updated: 2/8/1999
Victor A. McKusick - updated: 10/16/1998
*FIELD* CD
Victor A. McKusick: 8/22/1995
*FIELD* ED
carol: 09/16/2013
carol: 2/8/2013
terry: 2/8/2013
carol: 11/30/2011
joanna: 3/18/2004
carol: 9/17/2003
carol: 2/14/1999
terry: 2/8/1999
terry: 10/16/1998
mark: 4/19/1996
mimadm: 11/3/1995
mark: 8/22/1995
MIM
602242
*RECORD*
*FIELD* NO
602242
*FIELD* TI
*602242 ADAPTOR-RELATED PROTEIN COMPLEX 2, SIGMA-1 SUBUNIT; AP2S1
;;CLATHRIN-ASSOCIATED/ASSEMBLY/ADAPTOR PROTEIN, SMALL 2, 17-KD; CLAPS2;;
read moreCLATHRIN ADAPTOR PROTEIN AP17; AP17;;
CLATHRIN ADAPTOR COMPLEX AP2, SIGMA SUBUNIT
*FIELD* TX
DESCRIPTION
AP17 is the 17-kD component of the AP2 clathrin-associated protein
complex (see 601024).
CLONING
Winterpacht et al. (1996) cloned the AP17 gene, CLAPS2, from a human
kidney cDNA library using the rat gene as a probe. The cDNA encodes a
predicted 142-amino acid protein that is 98% homologous to that of rat.
Holzmann et al. (1998) identified additional CLAPS2 cDNAs and found that
the predicted human and rat proteins are identical. They also isolated
cDNAs corresponding to an alternatively spliced CLAPS2 transcript
encoding AP17-delta, a protein variant lacking 38 amino acids of AP17.
By quantitative PCR analysis of AP2S1 expression using total RNA derived
from human, Nesbit et al. (2013) observed ubiquitous expression, with
expression in kidney and parathyroids similar to that in other tissues
except for brain, where higher expression was seen.
MAPPING
Winterpacht et al. (1996) mapped the CLAPS2 gene to chromosome
19q13.2-q13.3 by fluorescence in situ hybridization.
In affected members of 2 unrelated 3-generation families segregating
autosomal dominant hypocalciuric hypercalcemia mapping to chromosome
19q13 (HHC3; 600740), Nesbit et al. (2013) identified heterozygosity for
a missense mutation in the AP2S1 gene (R15C; 602242.0001). Analysis of
AP2S1 in 50 unrelated patients with hypocalciuric hypercalcemia revealed
11 who were heterozygous for AP2S1 mutations, all of which involved the
R15 residue: R15C in 4 patients, R15L (602242.0002) in 4 patients, and
R15H (602242.0003) in 3 patients. Nesbit et al. (2013) suggested that
the R15 residue represents a mutation hotspot, and estimated that AP2S1
missense mutations involving R15 may be the underlying cause of HHC in
more than 20% of HHC patients without mutations in the CASR (601199)
gene. Functional analysis demonstrated that the AP2S1 mutations
decreased the sensitivity of CASR-expressing cells to extracellular
calcium and reduced CASR endocytosis, probably through loss of
interaction with a C-terminal CASR dileucine-based motif, the disruption
of which also decreased intracellular signaling.
*FIELD* AV
.0001
HYPOCALCIURIC HYPERCALCEMIA, FAMILIAL, TYPE III
AP2S1, ARG15CYS
In affected members of 2 unrelated 3-generation families segregating
autosomal dominant hypocalciuric hypercalcemia mapping to chromosome
19q13 (HHC3; 600740), 1 of which was a kindred from Oklahoma originally
described by McMurtry et al. (1992) and the other a kindred from
Northern Ireland originally reported by Nesbit et al. (2010), Nesbit et
al. (2013) identified heterozygosity for a C-T transition in exon 2 of
the AP2S1 gene, resulting in an arg15-to-cys (R15C) substitution at an
evolutionarily conserved residue. The R15C mutation was subsequently
identified in heterozygosity in 4 additional unrelated probands with
hypocalciuric hypercalcemia. Functional analysis in transiently
transfected HEK293 cells showed a rightward shift in Ca(2+)
concentration-response curves with the AP2S1 mutant compared to
wildtype, indicating a decrease in the sensitivity of cells expressing
CASR (601199) to extracellular calcium.
.0002
HYPOCALCIURIC HYPERCALCEMIA, FAMILIAL, TYPE III
AP2S1, ARG15LEU
In 4 unrelated probands with hypocalciuric hypercalcemia (HHC3; 600740),
Nesbit et al. (2013) identified heterozygosity for a G-T transversion in
exon 2 of the AP2S1 gene, resulting in an arg15-to-leu (R15L)
substitution at an evolutionarily conserved residue. Functional analysis
in transiently transfected HEK293 cells showed a rightward shift in
Ca(2+) concentration-response curves with the AP2S1 mutant compared to
wildtype, indicating a decrease in the sensitivity of cells expressing
CASR (601199) to extracellular calcium.
.0003
HYPOCALCIURIC HYPERCALCEMIA, FAMILIAL, TYPE III
AP2S1, ARG15HIS
In 3 unrelated probands with hypocalciuric hypercalcemia (HHC3; 600740),
Nesbit et al. (2013) identified heterozygosity for a G-A transition in
exon 2 of the AP2S1 gene, resulting in an arg15-to-his (R15H)
substitution at an evolutionarily conserved residue. Functional analysis
in transiently transfected HEK293 cells showed a rightward shift in
Ca(2+) concentration-response curves with the AP2S1 mutant compared to
wildtype, indicating a decrease in the sensitivity of cells expressing
CASR (601199) to extracellular calcium.
*FIELD* RF
1. Holzmann, K.; Poltl, A.; Sauermann, G.: A novel spliced transcript
of human CLAPS2 encoding a protein alternative to clathrin adaptor
protein AP17. Gene 220: 39-44, 1998.
2. McMurtry, C. T.; Schranck, F. W.; Walkenhorst, D. A.; Murphy, W.
A.; Kocher, D. B.; Teitelbaum, S. L.; Rupich, R. C.; Whyte, M. P.
: Significant developmental elevation in serum parathyroid hormone
levels in a large kindred with familial benign (hypocalciuric) hypercalcemia. Am.
J. Med. 93: 247-258, 1992.
3. Nesbit, M. A.; Hannan, F. M.; Graham, U.; Whyte, M. P.; Morrison,
P. J.; Hunter, S. J.; Thakker, R. V.: Identification of a second
kindred with familial hypocalciuric hypercalcemia type 3 (FHH3) narrows
localization to a less than 3.5 megabase pair region on chromosome
19q13.3. J. Clin. Endocr. Metab. 95: 1947-1954, 2010.
4. Nesbit, M. A.; Hannan, F. M.; Howles, S. A.; Reed, A. A. C.; Cranston,
T.; Thakker, C. E.; Gregory, L.; Rimmer, A. J.; Rust, N.; Graham,
U.; Morrison, P. J.; Hunter, S. J.; Whyte, M. P.; McVean, G.; Buck,
D.; Thakker, R. V.: Mutations in AP2S1 cause familial hypocalciuric
hypercalcemia type 3. Nature Genet. 45: 93-97, 2013.
5. Winterpacht, A.; Endele, S.; Enklaar, T.; Fuhry, M.; Zabel, B.
: Human CLAPS2 encoding AP17, a small chain of the clathrin-associated
protein complex: cDNA cloning and chromosomal assignment to 19q13.2-q13.3. Cytogenet.
Cell Genet. 75: 132-135, 1996.
*FIELD* CN
Marla J. F. O'Neill - updated: 08/12/2013
Marla J. F. O'Neill - updated: 2/8/2013
Rebekah S. Rasooly - updated: 2/15/1999
*FIELD* CD
Rebekah S. Rasooly: 1/8/1998
*FIELD* ED
carol: 08/12/2013
carol: 2/8/2013
terry: 2/8/2013
carol: 1/23/2013
carol: 4/11/2001
alopez: 2/15/1999
psherman: 1/5/1999
alopez: 1/9/1998
*RECORD*
*FIELD* NO
602242
*FIELD* TI
*602242 ADAPTOR-RELATED PROTEIN COMPLEX 2, SIGMA-1 SUBUNIT; AP2S1
;;CLATHRIN-ASSOCIATED/ASSEMBLY/ADAPTOR PROTEIN, SMALL 2, 17-KD; CLAPS2;;
read moreCLATHRIN ADAPTOR PROTEIN AP17; AP17;;
CLATHRIN ADAPTOR COMPLEX AP2, SIGMA SUBUNIT
*FIELD* TX
DESCRIPTION
AP17 is the 17-kD component of the AP2 clathrin-associated protein
complex (see 601024).
CLONING
Winterpacht et al. (1996) cloned the AP17 gene, CLAPS2, from a human
kidney cDNA library using the rat gene as a probe. The cDNA encodes a
predicted 142-amino acid protein that is 98% homologous to that of rat.
Holzmann et al. (1998) identified additional CLAPS2 cDNAs and found that
the predicted human and rat proteins are identical. They also isolated
cDNAs corresponding to an alternatively spliced CLAPS2 transcript
encoding AP17-delta, a protein variant lacking 38 amino acids of AP17.
By quantitative PCR analysis of AP2S1 expression using total RNA derived
from human, Nesbit et al. (2013) observed ubiquitous expression, with
expression in kidney and parathyroids similar to that in other tissues
except for brain, where higher expression was seen.
MAPPING
Winterpacht et al. (1996) mapped the CLAPS2 gene to chromosome
19q13.2-q13.3 by fluorescence in situ hybridization.
In affected members of 2 unrelated 3-generation families segregating
autosomal dominant hypocalciuric hypercalcemia mapping to chromosome
19q13 (HHC3; 600740), Nesbit et al. (2013) identified heterozygosity for
a missense mutation in the AP2S1 gene (R15C; 602242.0001). Analysis of
AP2S1 in 50 unrelated patients with hypocalciuric hypercalcemia revealed
11 who were heterozygous for AP2S1 mutations, all of which involved the
R15 residue: R15C in 4 patients, R15L (602242.0002) in 4 patients, and
R15H (602242.0003) in 3 patients. Nesbit et al. (2013) suggested that
the R15 residue represents a mutation hotspot, and estimated that AP2S1
missense mutations involving R15 may be the underlying cause of HHC in
more than 20% of HHC patients without mutations in the CASR (601199)
gene. Functional analysis demonstrated that the AP2S1 mutations
decreased the sensitivity of CASR-expressing cells to extracellular
calcium and reduced CASR endocytosis, probably through loss of
interaction with a C-terminal CASR dileucine-based motif, the disruption
of which also decreased intracellular signaling.
*FIELD* AV
.0001
HYPOCALCIURIC HYPERCALCEMIA, FAMILIAL, TYPE III
AP2S1, ARG15CYS
In affected members of 2 unrelated 3-generation families segregating
autosomal dominant hypocalciuric hypercalcemia mapping to chromosome
19q13 (HHC3; 600740), 1 of which was a kindred from Oklahoma originally
described by McMurtry et al. (1992) and the other a kindred from
Northern Ireland originally reported by Nesbit et al. (2010), Nesbit et
al. (2013) identified heterozygosity for a C-T transition in exon 2 of
the AP2S1 gene, resulting in an arg15-to-cys (R15C) substitution at an
evolutionarily conserved residue. The R15C mutation was subsequently
identified in heterozygosity in 4 additional unrelated probands with
hypocalciuric hypercalcemia. Functional analysis in transiently
transfected HEK293 cells showed a rightward shift in Ca(2+)
concentration-response curves with the AP2S1 mutant compared to
wildtype, indicating a decrease in the sensitivity of cells expressing
CASR (601199) to extracellular calcium.
.0002
HYPOCALCIURIC HYPERCALCEMIA, FAMILIAL, TYPE III
AP2S1, ARG15LEU
In 4 unrelated probands with hypocalciuric hypercalcemia (HHC3; 600740),
Nesbit et al. (2013) identified heterozygosity for a G-T transversion in
exon 2 of the AP2S1 gene, resulting in an arg15-to-leu (R15L)
substitution at an evolutionarily conserved residue. Functional analysis
in transiently transfected HEK293 cells showed a rightward shift in
Ca(2+) concentration-response curves with the AP2S1 mutant compared to
wildtype, indicating a decrease in the sensitivity of cells expressing
CASR (601199) to extracellular calcium.
.0003
HYPOCALCIURIC HYPERCALCEMIA, FAMILIAL, TYPE III
AP2S1, ARG15HIS
In 3 unrelated probands with hypocalciuric hypercalcemia (HHC3; 600740),
Nesbit et al. (2013) identified heterozygosity for a G-A transition in
exon 2 of the AP2S1 gene, resulting in an arg15-to-his (R15H)
substitution at an evolutionarily conserved residue. Functional analysis
in transiently transfected HEK293 cells showed a rightward shift in
Ca(2+) concentration-response curves with the AP2S1 mutant compared to
wildtype, indicating a decrease in the sensitivity of cells expressing
CASR (601199) to extracellular calcium.
*FIELD* RF
1. Holzmann, K.; Poltl, A.; Sauermann, G.: A novel spliced transcript
of human CLAPS2 encoding a protein alternative to clathrin adaptor
protein AP17. Gene 220: 39-44, 1998.
2. McMurtry, C. T.; Schranck, F. W.; Walkenhorst, D. A.; Murphy, W.
A.; Kocher, D. B.; Teitelbaum, S. L.; Rupich, R. C.; Whyte, M. P.
: Significant developmental elevation in serum parathyroid hormone
levels in a large kindred with familial benign (hypocalciuric) hypercalcemia. Am.
J. Med. 93: 247-258, 1992.
3. Nesbit, M. A.; Hannan, F. M.; Graham, U.; Whyte, M. P.; Morrison,
P. J.; Hunter, S. J.; Thakker, R. V.: Identification of a second
kindred with familial hypocalciuric hypercalcemia type 3 (FHH3) narrows
localization to a less than 3.5 megabase pair region on chromosome
19q13.3. J. Clin. Endocr. Metab. 95: 1947-1954, 2010.
4. Nesbit, M. A.; Hannan, F. M.; Howles, S. A.; Reed, A. A. C.; Cranston,
T.; Thakker, C. E.; Gregory, L.; Rimmer, A. J.; Rust, N.; Graham,
U.; Morrison, P. J.; Hunter, S. J.; Whyte, M. P.; McVean, G.; Buck,
D.; Thakker, R. V.: Mutations in AP2S1 cause familial hypocalciuric
hypercalcemia type 3. Nature Genet. 45: 93-97, 2013.
5. Winterpacht, A.; Endele, S.; Enklaar, T.; Fuhry, M.; Zabel, B.
: Human CLAPS2 encoding AP17, a small chain of the clathrin-associated
protein complex: cDNA cloning and chromosomal assignment to 19q13.2-q13.3. Cytogenet.
Cell Genet. 75: 132-135, 1996.
*FIELD* CN
Marla J. F. O'Neill - updated: 08/12/2013
Marla J. F. O'Neill - updated: 2/8/2013
Rebekah S. Rasooly - updated: 2/15/1999
*FIELD* CD
Rebekah S. Rasooly: 1/8/1998
*FIELD* ED
carol: 08/12/2013
carol: 2/8/2013
terry: 2/8/2013
carol: 1/23/2013
carol: 4/11/2001
alopez: 2/15/1999
psherman: 1/5/1999
alopez: 1/9/1998