RBCC Red Blood Cell Collection

VPS13B (CHS1, COH1, KIAA0532) [Confidence: low (only semi-automatic identification from reviews)]
Vacuolar protein sorting-associated protein 13B (Cohen syndrome protein 1)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt Q7Z7G8
ID VP13B_HUMAN Reviewed; 4022 AA.
AC Q7Z7G8; C9JD30; Q709C6; Q709C7; Q7Z7G4; Q7Z7G5; Q7Z7G6; Q7Z7G7;
read moreAC Q8NB77; Q9NWV1; Q9Y4E7;
DT 16-FEB-2004, integrated into UniProtKB/Swiss-Prot.
DT 05-OCT-2010, sequence version 2.
DT 22-JAN-2014, entry version 94.
DE RecName: Full=Vacuolar protein sorting-associated protein 13B;
DE AltName: Full=Cohen syndrome protein 1;
GN Name=VPS13B; Synonyms=CHS1, COH1, KIAA0532;
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] (ISOFORMS 1; 2; 3; 4 AND 5), TISSUE
RP SPECIFICITY, AND VARIANT COH1 ARG-2193.
RC TISSUE=Lymphoblast;
RX PubMed=12730828; DOI=10.1086/375454;
RA Kolehmainen J., Black G.C.M., Saarinen A., Chandler K.,
RA Clayton-Smith J., Traeskelin A.-L., Perveen R., Kivitie-Kallio S.,
RA Norio R., Warburg M., Fryns J.-P., de la Chapelle A., Lehesjoki A.-E.;
RT "Cohen syndrome is caused by mutations in a novel gene, COH1, encoding
RT a transmembrane protein with a presumed role in vesicle-mediated
RT sorting and intracellular protein transport.";
RL Am. J. Hum. Genet. 72:1359-1369(2003).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Lymphoblast;
RX PubMed=15498460; DOI=10.1016/j.ygeno.2004.04.012;
RA Velayos-Baeza A., Vettori A., Copley R.R., Dobson-Stone C.,
RA Monaco A.P.;
RT "Analysis of the human VPS13 gene family.";
RL Genomics 84:536-549(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 5), AND NUCLEOTIDE
RP SEQUENCE [LARGE SCALE MRNA] OF 518-1522 (ISOFORM 6).
RC TISSUE=Brain;
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=16421571; DOI=10.1038/nature04406;
RA Nusbaum C., Mikkelsen T.S., Zody M.C., Asakawa S., Taudien S.,
RA Garber M., Kodira C.D., Schueler M.G., Shimizu A., Whittaker C.A.,
RA Chang J.L., Cuomo C.A., Dewar K., FitzGerald M.G., Yang X.,
RA Allen N.R., Anderson S., Asakawa T., Blechschmidt K., Bloom T.,
RA Borowsky M.L., Butler J., Cook A., Corum B., DeArellano K.,
RA DeCaprio D., Dooley K.T., Dorris L. III, Engels R., Gloeckner G.,
RA Hafez N., Hagopian D.S., Hall J.L., Ishikawa S.K., Jaffe D.B.,
RA Kamat A., Kudoh J., Lehmann R., Lokitsang T., Macdonald P.,
RA Major J.E., Matthews C.D., Mauceli E., Menzel U., Mihalev A.H.,
RA Minoshima S., Murayama Y., Naylor J.W., Nicol R., Nguyen C.,
RA O'Leary S.B., O'Neill K., Parker S.C.J., Polley A., Raymond C.K.,
RA Reichwald K., Rodriguez J., Sasaki T., Schilhabel M., Siddiqui R.,
RA Smith C.L., Sneddon T.P., Talamas J.A., Tenzin P., Topham K.,
RA Venkataraman V., Wen G., Yamazaki S., Young S.K., Zeng Q.,
RA Zimmer A.R., Rosenthal A., Birren B.W., Platzer M., Shimizu N.,
RA Lander E.S.;
RT "DNA sequence and analysis of human chromosome 8.";
RL Nature 439:331-335(2006).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 2386-4022.
RC TISSUE=Brain;
RX PubMed=9628581; DOI=10.1093/dnares/5.1.31;
RA Nagase T., Ishikawa K., Miyajima N., Tanaka A., Kotani H., Nomura N.,
RA Ohara O.;
RT "Prediction of the coding sequences of unidentified human genes. IX.
RT The complete sequences of 100 new cDNA clones from brain which can
RT code for large proteins in vitro.";
RL DNA Res. 5:31-39(1998).
RN [6]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [7]
RP VARIANT COH1 SER-2993.
RX PubMed=15141358; DOI=10.1086/422197;
RA Kolehmainen J., Wilkinson R., Lehesjoki A.-E., Chandler K.,
RA Kivitie-Kallio S., Clayton-Smith J., Traeskelin A.-L., Waris L.,
RA Saarinen A., Khan J., Gross-Tsur V., Traboulsi E.I., Warburg M.,
RA Fryns J.-P., Norio R., Black G.C.M., Manson F.D.C.;
RT "Delineation of Cohen syndrome following a large-scale genotype-
RT phenotype screen.";
RL Am. J. Hum. Genet. 75:122-127(2004).
RN [8]
RP VARIANTS COH1 CYS-2341 AND ASP-2645.
RX PubMed=15154116; DOI=10.1086/422219;
RA Hennies H.C., Rauch A., Seifert W., Schumi C., Moser E., Al-Taji E.,
RA Tariverdian G., Chrzanowska K.H., Krajewska-Walasek M., Rajab A.,
RA Giugliani R., Neumann T.E., Eckl K.M., Karbasiyan M., Reis A.,
RA Horn D.;
RT "Allelic heterogeneity in the COH1 gene explains clinical variability
RT in Cohen syndrome.";
RL Am. J. Hum. Genet. 75:138-145(2004).
RN [9]
RP VARIANT COH1 THR-2820.
RX PubMed=15211651; DOI=10.1002/ajmg.a.30033;
RA Falk M.J., Feiler H.S., Neilson D.E., Maxwell K., Lee J.V.,
RA Segall S.K., Robin N.H., Wilhelmsen K.C., Traeskelin A.-L.,
RA Kolehmainen J., Lehesjoki A.-E., Wiznitzer M., Warman M.L.;
RT "Cohen syndrome in the Ohio Amish.";
RL Am. J. Med. Genet. A 128:23-28(2004).
RN [10]
RP VARIANTS COH1 1739-GLU--GLN-1744 DEL AND LEU-2773, AND VARIANTS
RP THR-829; ILE-866; VAL-1994; CYS-2822 AND ARG-3142.
RX PubMed=16648375; DOI=10.1136/jmg.2005.039867;
RA Seifert W., Holder-Espinasse M., Spranger S., Hoeltzenbein M.,
RA Rossier E., Dollfus H., Lacombe D., Verloes A., Chrzanowska K.H.,
RA Maegawa G.H.B., Chitayat D., Kotzot D., Huhle D., Meinecke P.,
RA Albrecht B., Mathijssen I., Leheup B., Raile K., Hennies H.C.,
RA Horn D.;
RT "Mutational spectrum of COH1 and clinical heterogeneity in Cohen
RT syndrome.";
RL J. Med. Genet. 43:E22-E22(2006).
RN [11]
RP VARIANT [LARGE SCALE ANALYSIS] VAL-3001.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S.,
RA Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J.,
RA Dawson D., Willson J.K.V., Gazdar A.F., Hartigan J., Wu L., Liu C.,
RA Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N.,
RA Vogelstein B., Kinzler K.W., Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal
RT cancers.";
RL Science 314:268-274(2006).
RN [12]
RP VARIANT COH1 LEU-1494 DEL, AND TISSUE SPECIFICITY.
RX PubMed=19006247; DOI=10.1002/humu.20886;
RA Seifert W., Holder-Espinasse M., Kuehnisch J., Kahrizi K.,
RA Tzschach A., Garshasbi M., Najmabadi H., Walter Kuss A., Kress W.,
RA Laureys G., Loeys B., Brilstra E., Mancini G.M.S., Dollfus H.,
RA Dahan K., Apse K., Hennies H.C., Horn D.;
RT "Expanded mutational spectrum in Cohen syndrome, tissue expression,
RT and transcript variants of COH1.";
RL Hum. Mutat. 30:E404-E420(2009).
RN [13]
RP VARIANT ILE-2481.
RX PubMed=23033978; DOI=10.1056/NEJMoa1206524;
RA de Ligt J., Willemsen M.H., van Bon B.W., Kleefstra T., Yntema H.G.,
RA Kroes T., Vulto-van Silfhout A.T., Koolen D.A., de Vries P.,
RA Gilissen C., del Rosario M., Hoischen A., Scheffer H., de Vries B.B.,
RA Brunner H.G., Veltman J.A., Vissers L.E.;
RT "Diagnostic exome sequencing in persons with severe intellectual
RT disability.";
RL N. Engl. J. Med. 367:1921-1929(2012).
CC -!- FUNCTION: May be involved in protein sorting in post Golgi
CC membrane traffic (By similarity).
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=6;
CC Name=1; Synonyms=1A;
CC IsoId=Q7Z7G8-1; Sequence=Displayed;
CC Name=2; Synonyms=2A;
CC IsoId=Q7Z7G8-2; Sequence=VSP_009408;
CC Name=3;
CC IsoId=Q7Z7G8-3; Sequence=VSP_009409, VSP_009410;
CC Name=4;
CC IsoId=Q7Z7G8-4; Sequence=VSP_009406, VSP_009407;
CC Name=5;
CC IsoId=Q7Z7G8-5; Sequence=VSP_009404, VSP_009405;
CC Note=Ref.1 (AAP41106) and Ref.3 (BAA91275) sequences differ from
CC that shown due to erroneous termination (Stop codon at position
CC 412);
CC Name=6;
CC IsoId=Q7Z7G8-6; Sequence=VSP_039837;
CC -!- TISSUE SPECIFICITY: Widely expressed. There is apparent
CC differential expression of different transcripts. In fetal brain,
CC lung, liver, and kidney, two transcripts of 2 and 5 kb are
CC identified. These transcripts are also seen in all adult tissues
CC analyzed. A larger transcript (12-14 kb) is expressed in prostate,
CC testis, ovary, and colon in the adult. Expression is very low in
CC adult brain tissue. Isoform 1 and isoform 2 are expressed in brain
CC and retina. Isoform 2 is expressed ubiquitously.
CC -!- DISEASE: Cohen syndrome (COH1) [MIM:216550]: A rare autosomal
CC recessive disorder characterized by obesity, hypotonia,
CC intellectual deficit, characteristic craniofacial dysmorphism and
CC abnormalities of the hands and feet. Characteristic facial
CC features include high-arched or wave-shaped eyelids, a short
CC philtrum, thick hair and low hairline. Note=The disease is caused
CC by mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the VPS13 family.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAC03664.1; Type=Erroneous initiation; Note=Translation N-terminally extended;
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/VPS13B";
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; AY223814; AAP41102.1; -; mRNA.
DR EMBL; AY223815; AAP41103.1; -; mRNA.
DR EMBL; AY223816; AAP41104.1; -; mRNA.
DR EMBL; AY223817; AAP41105.1; -; mRNA.
DR EMBL; AY223818; AAP41106.1; ALT_SEQ; mRNA.
DR EMBL; AJ608772; CAE75584.1; -; mRNA.
DR EMBL; AJ608773; CAE75585.1; -; mRNA.
DR EMBL; AK091431; BAC03664.1; ALT_INIT; mRNA.
DR EMBL; AK000590; BAA91275.1; ALT_SEQ; mRNA.
DR EMBL; AC018442; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC023933; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC026827; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC104986; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC105195; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC105328; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC107909; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AP004289; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AP004290; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AB011104; BAA25458.1; -; mRNA.
DR PIR; T00070; T00070.
DR RefSeq; NP_056058.2; NM_015243.2.
DR RefSeq; NP_060360.3; NM_017890.4.
DR RefSeq; NP_689777.3; NM_152564.4.
DR RefSeq; NP_858047.2; NM_181661.2.
DR RefSeq; XP_005250857.1; XM_005250800.1.
DR RefSeq; XP_005250858.1; XM_005250801.1.
DR RefSeq; XP_005250859.1; XM_005250802.1.
DR UniGene; Hs.191540; -.
DR ProteinModelPortal; Q7Z7G8; -.
DR IntAct; Q7Z7G8; 2.
DR PhosphoSite; Q7Z7G8; -.
DR DMDM; 308153515; -.
DR PaxDb; Q7Z7G8; -.
DR PRIDE; Q7Z7G8; -.
DR Ensembl; ENST00000355155; ENSP00000347281; ENSG00000132549.
DR Ensembl; ENST00000357162; ENSP00000349685; ENSG00000132549.
DR Ensembl; ENST00000358544; ENSP00000351346; ENSG00000132549.
DR Ensembl; ENST00000395996; ENSP00000379318; ENSG00000132549.
DR Ensembl; ENST00000441350; ENSP00000398472; ENSG00000132549.
DR Ensembl; ENST00000496144; ENSP00000430900; ENSG00000132549.
DR GeneID; 157680; -.
DR KEGG; hsa:157680; -.
DR UCSC; uc003yiv.4; human.
DR CTD; 157680; -.
DR GeneCards; GC08P100095; -.
DR HGNC; HGNC:2183; VPS13B.
DR HPA; HPA028146; -.
DR MIM; 216550; phenotype.
DR MIM; 607817; gene.
DR neXtProt; NX_Q7Z7G8; -.
DR Orphanet; 193; Cohen syndrome.
DR PharmGKB; PA26699; -.
DR eggNOG; COG5043; -.
DR HOVERGEN; HBG094148; -.
DR InParanoid; Q7Z7G8; -.
DR OMA; QRVEISI; -.
DR OrthoDB; EOG7HB58H; -.
DR PhylomeDB; Q7Z7G8; -.
DR ChiTaRS; VPS13B; human.
DR GenomeRNAi; 157680; -.
DR NextBio; 87507; -.
DR PRO; PR:Q7Z7G8; -.
DR ArrayExpress; Q7Z7G8; -.
DR Bgee; Q7Z7G8; -.
DR Genevestigator; Q7Z7G8; -.
DR GO; GO:0015031; P:protein transport; IEA:UniProtKB-KW.
DR InterPro; IPR015412; Autophagy-rel_C.
DR InterPro; IPR026854; VPS13A_N.
DR InterPro; IPR009543; VPSAP_dom.
DR Pfam; PF09333; ATG_C; 1.
DR Pfam; PF12624; Chorein_N; 1.
DR Pfam; PF06650; DUF1162; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Complete proteome; Disease mutation; Obesity;
KW Polymorphism; Protein transport; Reference proteome; Transport.
FT CHAIN 1 4022 Vacuolar protein sorting-associated
FT protein 13B.
FT /FTId=PRO_0000065880.
FT VAR_SEQ 403 415 LTEMQVESSYYSP -> VGLFSCCLYLYQL (in
FT isoform 5).
FT /FTId=VSP_009404.
FT VAR_SEQ 416 4022 Missing (in isoform 5).
FT /FTId=VSP_009405.
FT VAR_SEQ 839 863 GVKSKNPLPTLEGSIQNVELKYCST -> EIGSCYVAQVDL
FT ELLASNDPPTSTS (in isoform 4).
FT /FTId=VSP_009406.
FT VAR_SEQ 864 4022 Missing (in isoform 4).
FT /FTId=VSP_009407.
FT VAR_SEQ 977 977 Missing (in isoform 6).
FT /FTId=VSP_039837.
FT VAR_SEQ 1386 1433 SLGEECWSLGQCGGVFLSCTDKLNRRTLLVRPISKQDPFSN
FT CSGFFPS -> RPGEGWQSGHFEGVFLQCKEKSV (in
FT isoform 2).
FT /FTId=VSP_009408.
FT VAR_SEQ 1386 1427 SLGEECWSLGQCGGVFLSCTDKLNRRTLLVRPISKQDPFSN
FT C -> RPGEGWQSGHFEGVFLQCKEKSVPWGRVLVFGAMWR
FT CLPFLY (in isoform 3).
FT /FTId=VSP_009409.
FT VAR_SEQ 1428 4022 Missing (in isoform 3).
FT /FTId=VSP_009410.
FT VARIANT 829 829 A -> T (in dbSNP:rs61753721).
FT /FTId=VAR_058749.
FT VARIANT 866 866 V -> I.
FT /FTId=VAR_058750.
FT VARIANT 1138 1138 P -> L (in dbSNP:rs35342235).
FT /FTId=VAR_057750.
FT VARIANT 1494 1494 Missing (in COH1).
FT /FTId=VAR_058751.
FT VARIANT 1739 1744 Missing (in COH1).
FT /FTId=VAR_058752.
FT VARIANT 1994 1994 I -> V (in dbSNP:rs139640224).
FT /FTId=VAR_058753.
FT VARIANT 2193 2193 L -> R (in COH1; could be a rare
FT polymorphism).
FT /FTId=VAR_017759.
FT VARIANT 2341 2341 Y -> C (in COH1).
FT /FTId=VAR_038422.
FT VARIANT 2481 2481 V -> I (found in a patient with mental
FT retardation and facial dysmorphisms).
FT /FTId=VAR_069429.
FT VARIANT 2584 2584 V -> A (in dbSNP:rs7833870).
FT /FTId=VAR_057751.
FT VARIANT 2645 2645 G -> D (in COH1).
FT /FTId=VAR_038423.
FT VARIANT 2773 2773 S -> L (in COH1).
FT /FTId=VAR_058754.
FT VARIANT 2820 2820 I -> T (in COH1).
FT /FTId=VAR_058755.
FT VARIANT 2822 2822 Y -> C.
FT /FTId=VAR_058756.
FT VARIANT 2993 2993 N -> S (in COH1; dbSNP:rs28940272).
FT /FTId=VAR_038424.
FT VARIANT 3001 3001 L -> V (in a breast cancer sample;
FT somatic mutation).
FT /FTId=VAR_036325.
FT VARIANT 3142 3142 S -> R.
FT /FTId=VAR_058757.
FT VARIANT 3432 3432 G -> R (in dbSNP:rs6468694).
FT /FTId=VAR_057752.
FT CONFLICT 401 401 F -> S (in Ref. 3; BAA91275).
FT CONFLICT 544 544 M -> V (in Ref. 1; AAP41102/AAP41103/
FT AAP41104/AAP41105 and 3; BAC03664).
FT CONFLICT 618 618 D -> N (in Ref. 1; AAP41102/AAP41103/
FT AAP41104/AAP41105 and 3; BAC03664).
FT CONFLICT 1387 1387 L -> H (in Ref. 1; AAP41102).
FT CONFLICT 1401 1401 F -> I (in Ref. 1; AAP41102).
FT CONFLICT 1425 1425 S -> R (in Ref. 1; AAP41102).
FT CONFLICT 1673 1673 A -> D (in Ref. 1; AAP41102/AAP41103).
SQ SEQUENCE 4022 AA; 448664 MW; 35B79EE13730AFE3 CRC64;
MLESYVTPIL MSYVNRYIKN LKPSDLQLSL WGGDVVLSKL ELKLDVLEQE LKLPFTFLSG
HIHELRIHVP WTKLGSEPVV ITINTMECIL KLKDGIQDDH ESCGSNSTNR STAESTKSSI
KPRRMQQAAP TDPDLPPGYV QSLIRRVVNN VNIVINNLIL KYVEDDIVLS VNITSAECYT
VGELWDRAFM DISATDLVLR KVINFSDCTV CLDKRNASGK IEFYQDPLLY KCSFRTRLHF
TYENLNSKMP SVIKIHTLVE SLKLSITDQQ LPMFIRIMQL GIALYYGEIG NFKEGEIEDL
TCHNKDMLGN ITGSEDETRI DMQYPAQHKG QELYSQQDEE QPQGWVSWAW SFVPAIVSYD
DGEEDFVGND PASTMHQQKA QTLKDPIVSI GFYCTKATVT FKLTEMQVES SYYSPQKVKS
KEVLCWEQEG TTVEALMMGE PFFDCQIGFV GCRAMCLKGI MGVKDFEENM NRSETEACFF
ICGDNLSTKG FTYLTNSLFD YRSPENNGTR AEFILDSTHH KETYTEIAGM QRFGAFYMDY
LYTMENTSGK GSTNQQDFSS GKSEDLGTVQ EKSTKSLVIG PLDFRLDSSA VHRILKMIVC
ALEHEYEPYS RLKSDIKDEN ETILNPEEVA LLEEYIPTRH TSVTLLKCTC TISMAEFNLL
DHLLPVIMGE KNSSNFMNTT NFQSLRPLPS IRILVDKINL EHSVPMYAEQ LVHVVSSLTQ
PSDNLLHYCY VHCYLKIFGF QAGLTSLDCS GSYCLPVPVI PSFSTALYGK LLKLPTCWTK
RSQIAITEGI FELPNLTIQA TRAQTLLLQA IYQSWSHLGN VSSSAVIEAL INEIFLSIGV
KSKNPLPTLE GSIQNVELKY CSTSLVKCAS GTMGSIKICA KAPVDSGKEK LIPLLQGPSD
TKDLHSTKWL NESRKPESLL APDLMAFTIQ VPQYIDYCHN SGAVLLCSIQ GLAVNIDPIL
YTWLIYQPQK RTSRHMQQQP VVAVPLVMPV CRRKEDEVSI GSAPLAKQQS YQASEYASSP
VKTKTVTESR PLSVPVKAML NISESCRSPE ERMKEFIGIV WNAVKHLTLQ LEVQSCCVFI
PNDSLPSPST IVSGDIPGTV RSWYHGQTSM PGTLVLCLPQ IKIISAGHKY MEPLQEIPFV
IPRPILEEGD AFPWTISLHN FSIYTLLGKQ VTLCLVEPMG CTSTLAVTSQ KLLATGPDTR
HSFVVCLHVD LESLEIKCSN PQVQLFYELT DIMNKVWNKI QKRGNLNLSP TSPETMAGPV
PTSPVRSSIG TAPPDTSTCS PSADIGTTTE GDSIQAGEES PFSDSVTLEQ TTSNIGGTSG
RVSLWMQWVL PKITIKLFAP DPENKGTEVC MVSELEDLSA SIDVQDVYTK VKCKIESFNI
DHYRSSLGEE CWSLGQCGGV FLSCTDKLNR RTLLVRPISK QDPFSNCSGF FPSTTTKLLD
GTHQQHGFLS LTYTKAVTKN VRHKLTSRNE RRSFHKLSEG LMDGSPHFLH EILLSAQAFD
IVLYFPLLNA IASIFQAKLP KTQKEKRKSP GQPMRTHTLT SRNLPLIYVN TSVIRIFIPK
TEEMQPTVEA NQAAKEDTVV LKIGSVAMAP QADNPLGRSV LRKDIYQRAL NLGILRDPGS
EIEDRQYQID LQSINIGTAQ WHQLKPEKES VSGGVVTETE RNSQNPALEW NMASSIRRHQ
ERRAILTPVL TDFSVRITGA PAVIFTKVVS PENLHTEEIL VCGHSLEVNI TTNLDFFLSV
AQVQLLHQLI VANMTGLEPS NKAAEISKQE QKKVDIFDGG MAETSSRYSG AQDSGIGSDS
VKIRIVQIEQ HSGASQHRIA RPSRQSSIVK NLNFIPFDIF ITASRISLMT YSCMALSKSK
SQEQKNNEKT DKSSLNLPEV DSDVAKPNQA CISTVTAEDL LRSSISFPSG KKIGVLSLES
LHASTRSSAR QALGITIVRQ PGRRGTGDLQ LEPFLYFIVS QPSLLLSCHH RKQRVEVSIF
DAVLKGVASD YKCIDPGKTL PEALDYCTVW LQTVPGEIDS KSGIPPSFIT LQIKDFLNGP
ADVNLDISKP LKANLSFTKL DQINLFLKKI KNAHSLAHSE ETSAMSNTMV NKDDLPVSKY
YRGKLSKPKI HGDGVQKISA QENMWRAVSC FQKISVQTTQ IVISMETVPH TSKPCLLASL
SNLNGSLSVK ATQKVPGIIL GSSFLLSIND FLLKTSLKER SRILIGPCCA TANLEAKWCK
HSGNPGPEQS IPKISIDLRG GLLQVFWGQE HLNCLVLLHE LLNGYLNEEG NFEVQVSEPV
PQMSSPVEKN QTFKSEQSSD DLRTGLFQYV QDAESLKLPG VYEVLFYNET EDCPGMMLWR
YPEPRVLTLV RITPVPFNTT EDPDISTADL GDVLQVPCSL EYWDELQKVF VAFREFNLSE
SKVCELQLPD INLVNDQKKL VSSDLWRIVL NSSQNGADDQ SSASESGSQS TCDPLVTPTA
LAACTRVDSC FTPWFVPSLC VSFQFAHLEF HLCHHLDQLG TAAPQYLQPF VSDRNMPSEL
EYMIVSFREP HMYLRQWNNG SVCQEIQFLA QADCKLLECR NVTMQSVVKP FSIFGQMAVS
SDVVEKLLDC TVIVDSVFVN LGQHVVHSLN TAIQAWQQNK CPEVEELVFS HFVICNDTQE
TLRFGQVDTD ENILLASLHS HQYSWRSHKS PQLLHICIEG WGNWRWSEPF SVDHAGTFIR
TIQYRGRTAS LIIKVQQLNG VQKQIIICGR QIICSYLSQS IELKVVQHYI GQDGQAVVRE
HFDCLTAKQK LPSYILENNE LTELCVKAKG DEDWSRDVCL ESKAPEYSIV IQVPSSNSSI
IYVWCTVLTL EPNSQVQQRM IVFSPLFIMR SHLPDPIIIH LEKRSLGLSE TQIIPGKGQE
KPLQNIEPDL VHHLTFQARE EYDPSDCAVP ISTSLIKQIA TKVHPGGTVN QILDEFYGPE
KSLQPIWPYN KKDSDRNEQL SQWDSPMRVK LSIWKPYVRT LLIELLPWAL LINESKWDLW
LFEGEKIVLQ VPAGKIIIPP NFQEAFQIGI YWANTNTVHK SVAIKLVHNL TSPKWKDGGN
GEVVTLDEEA FVDTEIRLGA FPGHQKLCQF CISSMVQQGI QIIQIEDKTT IINNTPYQIF
YKPQLSVCNP HSGKEYFRVP DSATFSICPG GEQPAMKSSS LPCWDLMPDI SQSVLDASLL
QKQIMLGFSP APGADSSQCW SLPAIVRPEF PRQSVAVPLG NFRENGFCTR AIVLTYQEHL
GVTYLTLSED PSPRVIIHNR CPVKMLIKEN IKDIPKFEVY CKKIPSECSI HHELYHQISS
YPDCKTKDLL PSLLLRVEPL DEVTTEWSDA IDINSQGTQV VFLTGFGYVY VDVVHQCGTV
FITVAPEGKA GPILTNTNRA PEKIVTFKMF ITQLSLAVFD DLTHHKASAE LLRLTLDNIF
LCVAPGAGPL PGEEPVAALF ELYCVEICCG DLQLDNQLYN KSNFHFAVLV CQGEKAEPIQ
CSKMQSLLIS NKELEEYKEK CFIKLCITLN EGKSILCDIN EFSFELKPAR LYVEDTFVYY
IKTLFDTYLP NSRLAGHSTH LSGGKQVLPM QVTQHARALV NPVKLRKLVI QPVNLLVSIH
ASLKLYIASD HTPLSFSVFE RGPIFTTARQ LVHALAMHYA AGALFRAGWV VGSLDILGSP
ASLVRSIGNG VADFFRLPYE GLTRGPGAFV SGVSRGTTSF VKHISKGTLT SITNLATSLA
RNMDRLSLDE EHYNRQEEWR RQLPESLGEG LRQGLSRLGI SLLGAIAGIV DQPMQNFQKT
SEAQASAGHK AKGVISGVGK GIMGVFTKPI GGAAELVSQT GYGILHGAGL SQLPKQRHQP
SDLHADQAPN SHVKYVWKML QSLGRPEVHM ALDVVLVRGS GQEHEGCLLL TSEVLFVVSV
SEDTQQQAFP VTEIDCAQDS KQNNLLTVQL KQPRVACDVE VDGVRERLSE QQYNRLVDYI
TKTSCHLAPS CSSMQIPCPV VAAEPPPSTV KTYHYLVDPH FAQVFLSKFT MVKNKALRKG
FP
//

MIM 216550
*RECORD*
*FIELD* NO
216550
*FIELD* TI
#216550 COHEN SYNDROME; COH1
;;HYPOTONIA, OBESITY, AND PROMINENT INCISORS;;
PEPPER SYNDROME;;
read moreCHS1, FORMERLY
*FIELD* TX
A number sign (#) is used with this entry because of evidence that some
patients with Cohen syndrome have homozygous or compound heterozygous
mutations in the COH1 gene (VPS13B; 607817) on chromosome 8q22.

CLINICAL FEATURES

Cohen syndrome is one of the rare autosomal recessive disorders that are
overrepresented in the Finnish population (Norio, 2003). The phenotype
in Finnish patients is highly homogeneous, consisting of nonprogressive
mild to severe psychomotor retardation, motor clumsiness, microcephaly,
characteristic facial features, childhood hypotonia and joint laxity,
progressive retinochoroidal dystrophy, myopia, intermittent isolated
neutropenia, and a cheerful disposition. Characteristic facial features
include high-arched or wave-shaped eyelids, a short philtrum, thick
hair, and low hairline. Kolehmainen et al. (2003) stated that in
non-Finnish patients thought to have Cohen syndrome, a confusing
phenotypic variability prevails. Obesity, although frequently mentioned
as a characteristic finding, is insignificant. On the other hand, there
is no proof of retinochoroidal dystrophy or intermittent neutropenia in
reports of some patients. Chandler et al. (2003) studied 33 non-Finnish
patients with Cohen syndrome and concluded that Cohen syndrome has a
distinctive clinical phenotype identifiable not only in Finnish patients
but also in other genetically diverse patient groups.

Cohen et al. (1973) described a brother and sister and an unrelated
patient with hypotonia, obesity, high nasal bridge, and prominent
incisors as well as mental deficiency. Carey and Hall (1978) reported 4
additional patients. Sack and Friedman (1980) observed the syndrome in a
10-year-old girl with excessive height and floppy mitral valve.
Intrafamilial variability suggested that the diagnosis may often be
difficult. Kousseff (1981) described 4 affected sibs (2 of each sex)
with moderate mental retardation, microcephaly, hypotonia, high nasal
bridge, and narrow hands and feet with elongated fingers and toes. Three
sibs were short of stature. Friedman and Sack (1982) reported 5
additional cases in 4 families, strengthening the conclusion of
autosomal recessive inheritance. Mental retardation, high nasal bridge,
prominent central incisors with open mouth, maxillary malar hypoplasia,
and antimongoloid slant of the eyes were features. They suggested that
the disorder may have a relatively high frequency in Ashkenazi Jews.

Since 1968, Norio et al. (1984) had observed patients with the same
disorder, known by them as the 'Pepper syndrome,' from the family name.
By 1984, they found reports of 25 cases (Balestrazzi et al., 1980;
Goecke et al., 1982) and added 6 Finnish patients. Norio et al. (1984)
added chorioretinal dystrophy and granulocytopenia to the clinical
features and observed parental consanguinity in 2 instances.
Ophthalmologic findings included decreased visual acuity, hemeralopia
(see 310500 for a discussion of the use of the terms hemeralopia and
nyctalopia), constricted visual fields, chorioretinal dystrophy with
bull's-eye-like maculae and pigmentary deposits, optic atrophy, and
isoelectric electroretinogram.

Fuhrmann-Rieger et al. (1984) pointed out the similarities of the
Prader-Willi syndrome (176270) and Cohen syndrome. (See also Fraccaro et
al., 1983).

North et al. (1985) reported 6 cases in 4 sibships. Periureteric
obstruction and epilepsy were reported as possible new features. In
Israel, where the Cohen syndrome seems to be unusually frequent, Sack
and Friedman (1986) studied 39 patients in 32 families. Neutropenia and
chorioretinal dysplasia, 2 manifestations found in all Finnish patients
by Norio et al. (1984), were not found in any of these patients.
Incorrect diagnoses included Marfan syndrome, Sotos syndrome,
hypothyroidism, minimal brain dysfunction, and, most frequently, 'mental
retardation of an unknown cause,' illustrating the difficulty of being
certain of the diagnosis.

Young and Moore (1987) described 3 affected sibs. Abnormalities present
in all 3 children included mental retardation, hypotonia, and short
philtrum with open mouth and prominent lips. Whereas the 2 older sibs
had similar facies and an engaging personality, the youngest had a
different facial appearance and marked behavioral problems. Mehes et al.
(1988) found mitral valve prolapse and severe gastroesophageal reflux
with hiatal hernia in an affected girl aged 2 years and 4 months. These
observations, along with others previously reported, suggested that
Cohen syndrome may be a connective tissue disorder.

Kondo et al. (1990) described 2 affected brothers from a consanguineous
marriage who also had leukopenia and mottled retina. Kondo et al. (1990)
pointed out that mottled retina had been observed in 22 of 87 patients
and that it appears to be family- and ethnic-specific. Among 19 familial
cases, mottled retina was observed in all affected sibs from 5 families,
but in 13 families none of the affected sibs had mottled retinas. All
Finnish patients had the mottled retina, but this was noted in only 1 of
39 Jewish patients. Based on these observations, Kondo et al. (1990)
suggested that there are 2 alleles at the gene locus for the Cohen
syndrome: one for a Finnish type with mottled retina and the other for a
Jewish type without retinal anomalies. They concurred with Norio and
Raitta (1986) that the Mirhosseini-Holmes-Walton syndrome (268050) is
the same as Cohen syndrome, or at least an allelic disorder.

Steinlein et al. (1991) described 2 brothers with findings fitting the
diagnosis of both the Cohen and the Mirhosseini-Holmes-Walton syndromes
but also showing severe ocular manifestations. Tapetoretinal
degeneration was documented by histopathologic studies. The younger
brother suffered total retinal detachment bilaterally, requiring
enucleation.

Warburg et al. (1990) were of the opinion that a retinitis
pigmentosa-like tapetoretinal degeneration is an 'obligatory sign' in
patients with Cohen syndrome. Their patient also had granulocytopenia.

Massa et al. (1991) described isolated growth hormone deficiency in a
girl with Cohen syndrome. Satisfactory catch-up growth occurred after
treatment with biosynthetic human growth hormone. Fryns et al. (1991)
reported a successful pregnancy in a 26-year-old woman with presumed
Cohen syndrome. Her offspring had slight psychomotor retardation but was
not thought to have the Cohen syndrome.

Norio (1993) indicated that the diagnosis of Cohen syndrome is suggested
by the short philtrum (which is unable to cover the upper incisors),
prominent root of the nose, and prominent upper central incisors. The
feet are often small, and there is usually an increased space between
toes 1 and 2 ('sandal groove'). The neutropenia is intermittent and
harmless.

Higgins et al. (1994) demonstrated pyridoxine-responsive
hyper-beta-alaninemia in a 4-year-old girl with some features of Cohen
syndrome. She had crooked teeth, a small philtrum, narrow hands, and
global developmental delay. Ophthalmic examination was not reported and
there was no mention of obesity.

Schlichtemeier et al. (1994) described probable Cohen syndrome in
African American brother and sister. The brother, who presented at age
13 years with new-onset seizures, sagittal sinus thrombosis with
cerebral hemorrhage, and extensive venous thrombosis of the lower limbs,
showed combined deficiency of protein C, protein S, and antithrombin
III. Carotid aneurysm and tortuous descending aorta were also present.
Schlichtemeier et al. (1994) suggested that vasculopathy may be an
integral part of the Cohen syndrome.

North et al. (1995) reported the cases of identical female twins with
Cohen syndrome. They presented with retinal degeneration, obesity, and
mental retardation, and had the characteristic facial appearance.
Unusual features of the twins included tall stature, macrocephaly, and
transient cardiomyopathy during the first year of life. Precocious
puberty was present in both girls; the development of breast buds and
axillary hair was noted at the age 7.5 years.

Kivitie-Kallio et al. (1997) reported hematologic data on 26 Finnish
patients with Cohen syndrome. All had experienced periods of isolated
granulocytopenia from an early age. Granulocytopenia was mild to
moderate, noncyclic, and never fatal. Most patients suffered from
prolonged or repeated gingival or skin infections. In 16 patients
studied in detail, bone marrow examination showed a normo- or
hypercellular marrow, with a left-shifted granulopoiesis in 8 of the 16
patients. The response to adrenaline stimulation was subnormal in 12 of
14 and to hydrocortisone in 8 of 16 patients, but administration of
recombinant GCSF (138970) caused granulocytosis in the 3 patients
studied. No bone marrow malignancies were seen.

Olivieri et al. (1998) studied the bone marrow and the functional
properties of neutrophils obtained from peripheral blood or skin window
exudates from a patient with Cohen syndrome. Neutrophil adhesive
capability was greatly increased in this patient. Cytofluorometric
expression of CD11B (120980) and CD62L molecules were consistent with a
generalized neutrophil activation in vivo. The patient was a 22-year-old
girl with neutropenia and recurrent gingivitis. A tentative diagnosis of
Prader-Willi syndrome had been made in childhood. However, her features,
including obesity, hypotonia, microcephaly, chorioretinal dystrophy,
high nasal bridge, narrow hands and feet, narrow and high-arched palate,
and prominent central incisors, were more consistent with Cohen
syndrome.

In 3 patients with Cohen syndrome, Okamoto et al. (1998) found a
remarkably high level of urinary hyaluronic acid. They pointed out that
hyperhyaluronic aciduria is a characteristic finding in Werner syndrome
(277700) and some other conditions. Okamoto et al. (1998) suggested that
the basic defect in Cohen syndrome involves a metabolic abnormality in
the extracellular matrix.

Kivitie-Kallio et al. (1998) performed MRI on 18 patients with Cohen
syndrome and 26 healthy volunteers. The main finding was a relatively
enlarged corpus callosum. A relatively enlarged corpus callosum in a
microcephalic head and normal signal intensities of the gray and white
matters supports a clinical suspicion of Cohen syndrome.

Kivitie-Kallio et al. (1999) evaluated cardiac, endocrine, and
radiologic abnormalities in 22 patients of Finnish descent with Cohen
syndrome. No evidence for clinically significant mitral prolapse was
found; however, a decreased left ventricular function with advancing age
was identified. No significant endocrine abnormalities were found in
examination of pituitary, adrenal, and thyroid function. The patients
were either of normal height or were moderately short at all ages, often
associated with marked kyphosis. Truncal obesity was seen in 4 of the 22
patients. X-rays of the chest, lumbar and thoracic spine, long bones,
ankles, and metacarpophalangeal pattern profiles revealed kyphosis,
scoliosis, and calcaneo planovalgus as common features. Fingers of these
patients were slender but short with a characteristic
metacarpophalangeal pattern profile.

Horn et al. (2000) reported 2 brothers and a cousin from a multiply
consanguineous kindred of Lebanese descent with a syndrome of
microcephaly, progressive postnatal growth deficiency, mental
retardation, hypotonia, chorioretinal dystrophy, and myopia. The
severity of the condition varied among the affected family members.

Kivitie-Kallio et al. (2000) reported ophthalmologic findings from 22
Finnish patients with Cohen syndrome.

Hurmerinta et al. (2002) pointed to the fact that Cohen syndrome is
relatively common in Finland, where 35 patients had been diagnosed. They
obtained anthropometric measurements of the head and face of 22
patients, and cephalometric radiographs of 14 patients. Anthropometric
analysis confirmed and quantified the small head size. Width of the
upper face was close to normal but width of the lower face was small.
The philtrum was shorter than in healthy controls. Measurements from
standardized radiographs showed short cranial base dimensions but normal
cranial base angles. Most patients had forward-inclined upper incisors
and maxillary prognathia.

De Ravel et al. (2002) reevaluated a brother and sister, the offspring
of first cousins, who were originally reported by Buntinx et al. (1991)
as representing an apparently new syndrome of mental retardation, short
stature, unusual face, radioulnar synostosis, and retinal pigment
abnormalities. De Ravel et al. (2002) concluded that the 55-year-old
brother and 52-year-old sister had Cohen syndrome. Both had neutropenia
and the male had persistent fluctuating thrombocytopenia. De Ravel et
al. (2002) stated that asymptomatic thrombocytopenia had not previously
been reported in Cohen syndrome.

In their series of 33 non-Finnish patients with Cohen syndrome, Chandler
et al. (2003) identified laryngeal abnormalities, including
laryngomalacia, laryngeal stenosis, and vocal cord paralysis, as an
associated feature.

Karpf et al. (2004) reported findings on cognitive, linguistic, and
adaptive profiles in a group of 45 individuals clinically diagnosed with
Cohen syndrome at ages varying from 4 to 49 years. Independence levels
were generally poor, but socialization skills were relatively less
impaired. This particular area of strength was thought to underlie the
'sociable' temperament typically associated with Cohen syndrome. The
range of cognitive ability was wider in this study than reported in most
previous studies, raising the issue of whether mental retardation should
be considered a necessary component of the phenotype.

Kolehmainen et al. (2004) undertook an extensive molecular assessment of
76 patients from 59 families with a provisional diagnosis of Cohen
syndrome and correlated molecular and clinical findings. The patients
were assessed for the following 8 clinical criteria: developmental
delay, microcephaly, typical Cohen syndrome facial gestalt, truncal
obesity with slender extremities, overly sociable behavior, joint
hypermobility, high myopia and/or retinal dystrophy, and neutropenia.
Patients fulfilling 6 or more criteria were considered likely to have
true Cohen syndrome. Those with lower scores (5 of 8 or fewer) were
considered provisionally to have a Cohen-like syndrome. Kolehmainen et
al. (2004) found 22 different COH1 mutations, of which 19 were novel, in
probands identified by these diagnostic criteria. In addition, they
identified another 3 novel mutations in patients with incomplete
clinical data. By contrast, no COH1 mutations were found in patients
with a provisional diagnosis of Cohen syndrome who were labeled
'Cohen-like.'

Falk et al. (2004) described 8 members of 2 large Amish kindreds who had
early-onset pigmentary retinopathy and myopia, global developmental
delay and mental retardation, microcephaly, short stature, hypotonia,
joint hyperextensibility, small hands and feet, and a friendly
disposition. Several of the children had intermittent granulocytopenia.
Affected individuals shared a common facial appearance involving mild
synophrys, hypertelorism, wide and wave-shaped palpebral fissures, low
nasal bridge with a pinched root and bulbous tip, smooth philtrum, thin
upper lip, and hypotonic facies. They appeared to grimace when smiling.
Although the facial gestalt was considered inconsistent with the
diagnosis of Cohen syndrome, sequencing of the COH1 gene revealed
compound homozygosity in all affected individuals for both a frameshift
(607817.0009) and a missense (607817.0010) mutation in the COH1 gene.
Falk et al. (2004) concluded that facial gestalt is an unreliable
indicator of Cohen syndrome between ethnic populations, although it is
consistent among affected individuals within a particular ethnic group.

Waite et al. (2010) reported 3 patients, including 2 patients of
Pakistani descent from a consanguineous kindred who were distally
related, with genetically confirmed Cohen syndrome. All had the typical
facial appearance, developmental delay, and ocular anomalies, and all
also had cerebellar hypoplasia on brain imaging, which Waite et al.
(2010) concluded may be a feature of this disorder.

Rivera-Brugues et al. (2011) reported 3 patients with genetically
confirmed Cohen syndrome who were younger than 3 years of age. None had
neutropenia, and only 1 had mildly increased pigmentation of the retina.
Common features included hypotonic facial expression, almond-shaped
eyes, prominent nose, short philtrum, delayed psychomotor development,
and mental retardation. The authors noted that the facial phenotype and
some additional features of the disorder change with time.

DIAGNOSIS

Kivitie-Kallio and Norio (2001) reported the results of their nationwide
study of 29 patients with Cohen syndrome in Finland. They found the
following features to be essential for the diagnosis: nonprogressive
psychomotor retardation, motor clumsiness, and microcephaly; typical
facial features including high-arched eyelids, short philtrum, thick
hair, and low hairline; childhood hypotonia and hyperextensibility of
the joints; ophthalmologic findings of retinochoroidal dystrophy and
myopia in patients over 5 years of age; and periods of isolated
granulocytopenia. They noted a changing phenotype with age. In their
patients, psychomotor retardation was profound in 22%, severe in 61%,
moderate in 6%, and mild in 11%.

On the basis of a study of 33 non-Finnish patients with Cohen syndrome,
Chandler et al. (2003) contended that the diagnostic criteria suggested
by Kivitie-Kallio and Norio (2001) are important but not obligatory
features. As an aid to diagnosis, they proposed the presence of at least
2 of the following major criteria in a child with significant learning
difficulties: (1) facial gestalt, characterized by thick hair, eyebrows
and eyelashes, wave-shaped, downward-slanting palpebral fissures,
prominent, beak-shaped nose, short, upturned philtrum with grimacing
expression on smiling; (2) pigmentary retinopathy; and (3) neutropenia.
Less specific but supportive criteria included early-onset, progressive
myopia; microcephaly; truncal obesity with slender extremities; and
joint hyperextensibility.

MAPPING

In 2 brothers born of consanguineous parents, Kondo et al. (1990) found
that Cohen syndrome was not linked to markers in the 15q11-q12 region.

Tahvanainen et al. (1994) mapped the Cohen syndrome locus, symbolized
CHS1 by them, to chromosome 8 in an interval of approximately 10 cM
between D8S270 and D8S521. Both of these markers had been assigned to
8q22 (Wood et al., 1993). Their studies involved four 2-generation
Finnish pedigrees showing uniform clinical features in the affected
members. All the remaining 9 patients in Finland were isolated cases in
their families. Although not of value for linkage studies, they would be
fully informative for the analysis of linkage disequilibrium and
haplotype associations. In the Finnish population, one might anticipate
a single founding chromosome carrying the disease mutation. Tahvanainen
et al. (1994) suggested that the linkage information may help establish
or rule out genetic heterogeneity of Cohen syndrome, including answering
the question as to whether the ocular findings and leukopenia indicate a
separate entity.

By linkage disequilibrium analysis, Kolehmainen et al. (1997) narrowed
the COH1 region to the immediate vicinity of D8S1762. Haplotype analysis
suggested the occurrence of 1 main COH1 mutation and possibly 1 or 2
rare ones in Finland.

By homozygosity mapping in a consanguineous Lebanese kindred, Horn et
al. (2000) localized the gene responsible for this condition to a
26.8-cM region on chromosome 8q21.3-q22.1. This region overlapped the
refined gene region for Cohen syndrome (Kolehmainen et al., 1997). Horn
et al. (2000) hypothesized that the syndrome in their family, Cohen
syndrome, and Mirhosseini-Holmes-Walton syndrome may be allelic.

Segregation analysis in 11 non-Finnish families with Cohen syndrome by
Chandler et al. (2003) was consistent with linkage of the disorder to
the COH1 critical region on chromosome 8.

- Genetic Heterogeneity

Fryns et al. (1990) described a 15-year-old girl with features of Cohen
syndrome and a de novo, apparently balanced reciprocal translocation
t(5q;7p)(q33.1;p15.1). They suggested that the Cohen syndrome may be due
to a mutation in a gene located at either 5q33.1 or 7p15.1.

MOLECULAR GENETICS

By haplotype analysis, Kolehmainen et al. (2003) refined the critical
Cohen syndrome region on 8q22 and characterized a novel gene, COH1, that
is mutated in patients with Cohen syndrome (see
607817.0001-607817.0003). In 1 non-Finnish patient with Cohen syndrome
studied by Kolehmainen et al. (2003), no mutation was found in the COH1
gene, suggesting genetic heterogeneity.

By segregation analysis in 11 non-Finnish families with Cohen syndrome,
Chandler et al. (2003) demonstrated allele sharing in affected but not
unaffected sibs within the COH1 critical region. Haplotype analysis
suggested the presence of allelic heterogeneity.

Seifert et al. (2006) studied 24 patients with Cohen syndrome from 16
families of varying ethnic backgrounds and identified 25 different
mutations in the COH1 gene, including 9 nonsense mutations, 8 frameshift
mutations, 4 verified splice site mutations, 3 larger in-frame
deletions, and 1 missense mutation. There was marked variability of
developmental and growth parameters, although the typical facial gestalt
was seen in 23 of 24 patients. Early-onset progressive myopia was
present in all the patients older than 5 years, with widespread
pigmentary retinopathy seen in 12 of 14 patients assessed who were over
5 years of age.

Katzaki et al. (2007) identified pathogenic mutations in the COH1 gene
in 10 Italian patients with Cohen syndrome from 9 families. All patients
had characteristic features of the disorder, although with greater
variability than reported for Finnish patients. Heterozygous partial
COH1 gene deletions were identified in 2 different families.

In 14 individuals with Cohen syndrome from an isolated population on 2
small adjacent islands in the eastern part of the Greek archipelago,
Bugiani et al. (2008) identified a large homozygous deletion of exon 6
through 16 in the VPS13B gene (607817.0011). Twelve of the patients
belonged to a large consanguineous kindred. The phenotype was relatively
homogeneous, with common features including moderate to severe mental
retardation, slender extremities with narrow hands and feet, joint
hypermobility, and the typical facial gestalt. Microcephaly was not as
profound as reported in Finnish patients.

Parri et al. (2010) used multiplex ligation-dependent probe
amplification (MLPA) to analyze the VPS13B gene in 14 patients with
Cohen syndrome from 11 families, including 4 patients from 3 families
previously studied by Katzaki et al. (2007). All 14 patients displayed
the typical Cohen facial gestalt, narrow extremities, and truncal
adiposity, and microcephaly was present in 9 of the 14 patients. Parri
et al. (2010) detected 12 different mutations, including 6 frameshift, 3
splice site, and 2 nonsense mutations, as well as 1 complex
rearrangement. Four patients from 3 Italian families carried the same
large deletion of exon 6 through 16 previously identified in Greek
patients by Bugiani et al. (2008). Haplotype analysis of 1 of the Greek
patients as well as the 4 Italian patients suggested that the recurrent
deletion is due to an ancestral founder effect in the Mediterranean
area.

Using high-density oligonucleotide array data to analyze copy number
variation (CNV), Rivera-Brugues et al. (2011) found that 3 of 1,523
patients with unexplained mental retardation had intragenic heterozygous
deletions in the COH1 gene. Subsequent sequencing of the COH1 gene
revealed point mutations in the second allele in all 3 patients. No CNVs
involving the COH1 gene were found in 1,612 controls. The report was an
example of how microarrays can be used to identify autosomal recessive
syndromes and to extend the phenotypic and mutational spectrum of
recessive disorders.

NOMENCLATURE

The preferred symbol for Cohen syndrome is COH1 because the symbol CHS1
had already been established for Chediak-Higashi syndrome (214500).

*FIELD* RF
1. Balestrazzi, P.; Corrini, L.; Villani, G.; Bolla, M. P.; Casa,
F.; Bernasconi, S.: The Cohen syndrome: clinical and endocrinological
studies of two new cases. J. Med. Genet. 17: 430-432, 1980.

2. Bugiani, M.; Gyftodimou, Y.; Tsimpouka, P.; Lamantea, E.; Katzaki,
E.; d'Adamo, P.; Nakou, S.; Georgoudi, N.; Grigoriadou, M.; Tsina,
E.; Kabolis, N.; Milani, D.; Pandelia, E.; Kokotas, H.; Gasparini,
P.; Giannoulia-Karantana, A.; Renieri, A.; Zeviani, M.; Petersen,
M. B.: Cohen syndrome resulting from a novel large intragenic COH1
deletion segregating in an isolated Greek island population. Am.
J. Med. Genet. 146A: 2221-2226, 2008.

3. Buntinx, I. M.; Lormans, J. A. G.; Martin, J. J.; Dumon, J. E.
: A new association of mental retardation, short stature, unusual
face, radio-ulnar synostosis and retinal pigment abnormalities. Genet.
Counsel. 2: 237-240, 1991.

4. Carey, J. C.; Hall, B. D.: Confirmation of the Cohen syndrome. J.
Pediat. 93: 239-244, 1978.

5. Chandler, K. E.; Kidd, A.; Al-Gazali, L.; Kolehmainen, J.; Lehesjoki,
A.-E.; Black, G. C. M.; Clayton-Smith, J.: Diagnostic criteria, clinical
characteristics, and natural history of Cohen syndrome. J. Med. Genet. 40:
233-241, 2003.

6. Cohen, M. M., Jr.; Hall, B. D.; Smith, D. W.; Graham, C. B.; Lampert,
K. J.: A new syndrome with hypotonia, obesity, mental deficiency,
and facial, oral, ocular and limb anomalies. J. Pediat. 83: 280-284,
1973.

7. De Ravel, T. J. L.; Dillen, K.; Fryns, J. P.: A new association
of mental retardation, short stature, unusual face, radio-ulnar synostosis
and retinal pigment abnormalities: Cohen syndrome with thrombocytopenia.
(Letter) Genet. Counsel. 13: 475-476, 2002.

8. Falk, M. J.; Feiler, H. S.; Neilson, D. E.; Maxwell, K.; Lee, J.
V.; Segall, S. K.; Robin, N. H.; Wilhelmsen, K. C.; Traskelin, A.-L.;
Kolehmainen, J.; Lehesjoki, A.-E.; Wiznitzer, M.; Warman, M. L.:
Cohen syndrome in the Ohio Amish. Am. J. Med. Genet. 128A: 23-28,
2004.

9. Fraccaro, M.; Zuffardi, O.; Buhler, E.; Schinzel, A.; Simoni, G.;
Witkowski, R.; Bonifaci, E.; Caufin, D.; Cignacco, G.; Delendi, N.;
Gargantini, L.; Losanowa, T.; Marca, L.; Ullrich, E.; Vigi, V.: Deficiency,
transposition, and duplication of one 15q region may be alternatively
associated with Prader-Willi (or a similar) syndrome: analysis of
seven cases after varying ascertainment. Hum. Genet. 64: 388-394,
1983.

10. Friedman, E.; Sack, J.: The Cohen syndrome: report of five new
cases and a review of the literature. J. Craniofac. Genet. Dev. Biol. 2:
193-200, 1982.

11. Fryns, J.-P.; Kleczkowska, A.; Smeets, E.; Thiry, P.; Geutjens,
J.; Van den Berghe, H.: Cohen syndrome and de novo reciprocal translocation
t(5;7)(q33.1;p15.1). Am. J. Med. Genet. 37: 546-547, 1990.

12. Fryns, J. P.; Lemmens, F.; van den Berghe, H.: Cohen syndrome:
fertility in a female patient. Clin. Genet. 40: 461-464, 1991.

13. Fuhrmann-Rieger, A.; Kohler, A.; Fuhrmann, W.: Duplication or
insertion in 15q11-13 associated with mental retardation--short stature
and obesity--Prader-Willi or Cohen syndrome? Clin. Genet. 25: 347-352,
1984.

14. Goecke, T.; Majewski, F.; Kauther, K. D.; Sterzel, U.: Mental
retardation, hypotonia, obesity, ocular, facial, dental, and limb
abnormalities (Cohen syndrome); report of three patients. Europ.
J. Pediat. 138: 338-340, 1982.

15. Higgins, J. J.; Kaneski, C. R.; Bernardini, I.; Brady, R. O.;
Barton, N. W.: Pyridoxine-responsive hyper-beta-alaninemia associated
with Cohen's syndrome. Neurology 44: 1728-1732, 1994.

16. Horn, D.; Krebsova, A.; Kunze, J.; Reis, A.: Homozygosity mapping
in a family with microcephaly, mental retardation, and short stature
to a Cohen syndrome region on 8q21.3-8q22.1: redefining a clinical
entity. Am. J. Med. Genet. 92: 285-292, 2000.

17. Hurmerinta, K.; Pirinen, S.; Kovero, O.; Kivitie-Kallio, S.:
Craniofacial features in Cohen syndrome: an anthropometric and cephalometric
analysis of 14 patients. Clin. Genet. 62: 157-164, 2002.

18. Karpf, J.; Turk, J.; Howlin, P.: Cognitive, language, and adaptive
behavior profiles in individuals with a diagnosis of Cohen syndrome. Clin.
Genet. 65: 327-332, 2004.

19. Katzaki, E.; Pescucci, C.; Uliana, V.; Papa, F. T.; Ariani, F.;
Meloni, I.; Priolo, M.; Selicorni, A.; Milani, D.; Fischetto, R.;
Celle, M. E.; Grasso, R.; Dallapiccola, B.; Brancati, F.; Bordignon,
M.; Tenconi, R.; Federico, A.; Mari, F.; Renieri, A.; Longo, I.:
Clinical and molecular characterization of Italian patients affected
by Cohen syndrome. J. Hum. Genet. 52: 1011-1017, 2007. Note: Erratum:
J. Hum. Genet. 53: 285 only, 2008.

20. Kivitie-Kallio, S.; Autti, T.; Salonen, O.; Norio, R.: MRI of
the brain in the Cohen syndrome: a relatively large corpus callosum
in patients with mental retardation and microcephaly. Neuropediatrics 29:
298-301, 1998.

21. Kivitie-Kallio, S.; Eronen, M.; Lipsanen-Nyman, M.; Marttinen,
E.; Norio, R.: Cohen syndrome: evaluation of its cardiac, endocrine
and radiological features. Clin. Genet. 56: 41-50, 1999.

22. Kivitie-Kallio, S.; Norio, R.: Cohen syndrome: essential features,
natural history, and heterogeneity. Am. J. Med. Genet. 102: 125-135,
2001.

23. Kivitie-Kallio, S.; Rajantie, J.; Juvonen, E.; Norio, R.: Granulocytopenia
in Cohen syndrome. Brit. J. Haemat. 98: 308-311, 1997.

24. Kivitie-Kallio, S.; Summanen, P.; Raitta, C.; Norio, R.: Ophthalmologic
findings in Cohen syndrome: a long-term follow-up. Ophthalmology 107:
1737-1745, 2000.

25. Kolehmainen, J.; Black, G. C. M.; Saarinen, A.; Chandler, K.;
Clayton-Smith, J.; Traskelin, A.-L.; Perveen, R.; Kivitie-Kallio,
S.; Norio, R.; Warburg, M.; Fryns, J.-P.; de la Chapelle, A.; Lehesjoki,
A.-E.: Cohen syndrome is caused by mutations in a novel gene, COH1,
encoding a transmembrane protein with a presumed role in vesicle-mediated
sorting and intracellular protein transport. Am. J. Hum. Genet. 72:
1359-1369, 2003.

26. Kolehmainen, J.; Norio, R.; Kivitie-Kallio, S.; Tahvanainen, E.;
de la Chapelle, A.; Lehesjoki, A.-E.: Refined mapping of the Cohen
syndrome gene by linkage disequilibrium. Europ. J. Hum. Genet. 5:
206-213, 1997.

27. Kolehmainen, J.; Wilkinson, R.; Lehesjoki, A.-E.; Chandler, K.;
Kivitie-Kallio, S.; Clayton-Smith, J.; Traskelin, A.-L.; Waris, L.;
Saarinen, A.; Khan, J.; Gross-Tsur, V.; Traboulsi, E. I.; Warburg,
M.; Fryns, J.-P.; Norio, R.; Black, G. C. M.; Manson, F. D. C.: Delineation
of Cohen syndrome following a large-scale genotype-phenotype screen. Am.
J. Hum. Genet. 75: 122-127, 2004.

28. Kondo, I.; Hamabe, J.; Yamamoto, K.; Niikawa, N.: Exclusion mapping
of the Cohen syndrome gene from the Prader-Willi syndrome locus. Clin.
Genet. 38: 422-426, 1990.

29. Kondo, I.; Nagataki, S.; Miyagi, N.: The Cohen syndrome: does
mottled retina separate a Finnish and a Jewish type? Am. J. Med.
Genet. 37: 109-113, 1990.

30. Kousseff, B. G.: Cohen syndrome: further delineation and inheritance. Am.
J. Med. Genet. 9: 25-30, 1981.

31. Massa, G.; Dooms, L.; Vanderschueren-Lodeweyckx, M.: Growth hormone
deficiency in a girl with the Cohen syndrome. J. Med. Genet. 28:
48-50, 1991.

32. Mehes, K.; Kosztolanyi, G.; Kardos, M.; Horvath, M.: Cohen syndrome:
a connective tissue disorder? Am. J. Med. Genet. 31: 131-133, 1988.

33. Norio, R.: Personal Communication. Helsinki, Finland 5/29/1993.

34. Norio, R.: The Finnish disease heritage. I. Characteristics,
causes, background. Hum. Genet. 112: 441-456, 2003.

35. Norio, R.; Raitta, C.: Are the Mirhosseini-Holmes-Walton syndrome
and the Cohen syndrome identical? Am. J. Med. Genet. 25: 397-398,
1986.

36. Norio, R.; Raitta, C.; Lindahl, E.: Further delineation of the
Cohen syndrome; report on chorioretinal dystrophy, leukopenia and
consanguinity. Clin. Genet. 25: 1-14, 1984.

37. North, C.; Patton, M. A.; Baraitser, M.; Winter, R. M.: The clinical
features of the Cohen syndrome: further case reports. J. Med. Genet. 22:
131-134, 1985.

38. North, K. N.; Fulton, A. B.; Whiteman, D. A. H.: Identical twins
with Cohen syndrome. Am. J. Med. Genet. 58: 54-58, 1995.

39. Okamoto, N.; Hatsukawa, Y.; Arai, H.; Goto, M.: Cohen syndrome
with high urinary excretion of hyaluronic acid. Am. J. Med. Genet. 76:
387-388, 1998.

40. Olivieri, O.; Lombardi, S.; Russo, C.; Corrocher, R.: Increased
neutrophil adhesive capability in Cohen syndrome, an autosomal recessive
disorder associated with granulocytopenia. Haematologica 83: 778-782,
1998.

41. Parri, V.; Katzaki, E.; Uliana, V.; Scionti, F.; Tita, R.; Artuso,
R.; Longo, I.; Boschloo, R.; Vijzelaar, R.; Selecorni, A.; Brancati,
F.; Dallapiccola, B.; and 15 others: High frequency of COH1 intragenic
deletions and duplications detected by MLPA in patients with Cohen
syndrome. Europ. J. Hum. Genet. 18: 1133-1140, 2010.

42. Rivera-Brugues, N.; Albrecht, B.; Wieczorek, D.; Schmidt, H.;
Keller, T.; Gohring, I.; Ekici, A. B.; Tzschach, A.; Garshasbi, M.;
Franke, K.; Klopp, N.; Wichmann, H.-E.; Meitinger, T.; Strom, T. M.;
Hempel, M.: Cohen syndrome diagnosis using whole genome arrays. J.
Med. Genet. 48: 136-140, 2011.

43. Sack, J.; Friedman, E.: Cardiac involvement in the Cohen syndrome:
a case report. Clin. Genet. 17: 317-319, 1980.

44. Sack, J.; Friedman, E.: The Cohen syndrome in Israel. Israel
J. Med. Sci. 22: 766-770, 1986.

45. Schlichtemeier, T. L.; Tomlinson, G. E.; Kamen, B. A.; Waber,
L. J.; Wilson, G. N.: Multiple coagulation defects and the Cohen
syndrome. Clin. Genet. 45: 212-216, 1994.

46. Seifert, W.; Holder-Espinasse, M.; Spranger, S.; Hoeltzenbein,
M.; Rossier, E.; Dollfus, H.; Lacombe, D.; Verloes, A.; Chrzanowska,
K. H.; Maegawa, G. H. B.; Chitayat, D.; Kotzot, D.; Huhle, D.; Meinecke,
P.; Albrecht, B.; Mathijssen, I.; Leheup, B.; Raile, K.; Hennies,
H. C.; Horn, D.: Mutational spectrum of COH1 and clinical heterogeneity
in Cohen syndrome. (Letter) J. Med. Genet. 43: e22, 2006. Note:
Electronic Article.

47. Steinlein, O.; Tariverdian, G.; Boll, H. U.; Vogel, F.: Tapetoretinal
degeneration in brothers with apparent Cohen syndrome: nosology with
Mirhosseini-Holmes-Walton syndrome. Am. J. Med. Genet. 41: 196-200,
1991.

48. Tahvanainen, E.; Norio, R.; Karila, E.; Ranta, S.; Weissenbach,
J.; Sistonen, P.; de la Chapelle, A.: Cohen syndrome gene assigned
to the long arm of chromosome 8 by linkage analysis. Nature Genet. 7:
201-204, 1994.

49. Waite, A.; Somer, M.; O'Driscoll, M.; Millen, K.; Manson, F. D.
C.; Chandler, K. E.: Cerebellar hypoplasia and Cohen syndrome: a
confirmed association. (Letter) Am. J. Med. Genet. 152A: 2390-2393,
2010.

50. Warburg, M.; Pedersen, S. A.; Horlyk, H.: The Cohen syndrome:
retinal lesions and granulocytopenia. Ophthalmic Paediat. Genet. 11:
7-13, 1990.

51. Wood, S.; Ben Othmane, K.; Bergerheim, U. S. R.; Blanton, S. H.;
Bookstein, R.; Clarke, R. A.; Daiger, S. P.; Donis-Keller, H.; Drayna,
D.; Kumar, S.; Leach, R. J.; Ludecke, H.-J.; and 9 others: Report
of the first international workshop on human chromosome 8 mapping. Cytogenet.
Cell Genet. 64: 134-141, 1993.

52. Young, I. D.; Moore, J. R.: Intrafamilial variation in Cohen
syndrome. J. Med. Genet. 24: 488-492, 1987.

*FIELD* CS
INHERITANCE:
Autosomal recessive

GROWTH:
[Height];
Short stature;
[Weight];
Truncal obesity developing in mid-childhood;
Low birth weight

HEAD AND NECK:
[Head];
Microcephaly;
[Face];
Short philtrum;
Maxillary hypoplasia;
Mild micrognathia;
Facial hypotonia;
[Eyes];
Down slanting palpebral fissures;
Almond-shaped eyes;
Chorioretinal dystrophy;
Myopia;
Decreased visual acuity;
Optic atrophy;
[Nose];
Prominent nasal bridge;
[Mouth];
High, narrow palate;
Open mouth appearance;
[Teeth];
Prominent upper central incisors

CARDIOVASCULAR:
[Heart];
Mitral valve prolapse

SKELETAL:
[Spine];
Mild lumbar lordosis;
Mild thoracic scoliosis;
[Limbs];
Joint hyperextensibility;
Cubitus valgus;
Genu valgum;
[Hands];
Narrow hands;
Mild shortening of metacarpals;
Transverse palmar creases;
[Feet];
Narrow feet;
Mild shortening of metatarsals

SKIN, NAILS, HAIR:
[Skin];
Transverse palmar creases

NEUROLOGIC:
[Central nervous system];
Mental retardation;
Hypotonia;
Seizures;
Delayed motor milestones;
Large corpus callosum;
Cerebellar hypoplasia

ENDOCRINE FEATURES:
Delayed puberty;
Growth hormone deficiency

HEMATOLOGY:
Leukopenia;
Neutropenia

MISCELLANEOUS:
Cheerful disposition;
Increased frequency in Ashkenazi Jewish population and in Finland

MOLECULAR BASIS:
Caused by mutation in the homolog of the yeast vacuolar protein sorting
13 gene (VPS13B, 607817.0001)

*FIELD* CN
Cassandra L. Kniffin - updated: 6/15/2011
Cassandra L. Kniffin - updated: 2/23/2011
Kelly A. Przylepa - updated: 9/15/2003
Kelly A. Przylepa - revised: 8/14/2001

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
joanna: 05/01/2012
joanna: 2/9/2012
ckniffin: 6/15/2011
ckniffin: 2/23/2011
joanna: 2/2/2009
joanna: 3/30/2004
joanna: 9/15/2003
joanna: 8/14/2001

*FIELD* CN
Cassandra L. Kniffin - updated: 6/15/2011
Cassandra L. Kniffin - updated: 2/23/2011
Marla J. F. O'Neill - updated: 11/9/2010
Cassandra L. Kniffin - updated: 12/8/2008
Cassandra L. Kniffin - updated: 5/5/2008
Marla J. F. O'Neill - updated: 9/14/2006
Marla J. F. O'Neill - updated: 7/21/2004
Victor A. McKusick - updated: 6/30/2004
Victor A. McKusick - updated: 4/22/2004
Marla J. F. O'Neill - updated: 1/12/2004
Cassandra L. Kniffin - reorganized: 5/22/2003
Victor A. McKusick - updated: 5/21/2003
Victor A. McKusick - updated: 3/3/2003
Victor A. McKusick - updated: 11/25/2002
Sonja A. Rasmussen - updated: 8/23/2001
Sonja A. Rasmussen - updated: 7/17/2000
Victor A. McKusick - updated: 9/8/1999
Victor A. McKusick - updated: 8/30/1999
Victor A. McKusick - updated: 6/2/1999
Victor A. McKusick - updated: 2/27/1999
Victor A. McKusick - updated: 4/20/1998
Victor A. McKusick - updated: 10/30/1997
Victor A. McKusick - updated: 10/10/1997

*FIELD* CD
Victor A. McKusick: 6/3/1986

*FIELD* ED
terry: 12/20/2012
wwang: 6/30/2011
ckniffin: 6/15/2011
wwang: 2/24/2011
ckniffin: 2/23/2011
terry: 12/8/2010
wwang: 11/16/2010
terry: 11/9/2010
terry: 10/13/2010
carol: 8/30/2010
wwang: 1/7/2009
ckniffin: 12/8/2008
wwang: 5/14/2008
ckniffin: 5/5/2008
terry: 11/15/2006
wwang: 9/15/2006
terry: 9/14/2006
terry: 4/18/2005
tkritzer: 7/23/2004
terry: 7/21/2004
alopez: 7/19/2004
terry: 6/30/2004
tkritzer: 4/23/2004
terry: 4/22/2004
carol: 1/12/2004
carol: 5/22/2003
ckniffin: 5/22/2003
carol: 5/22/2003
terry: 5/21/2003
carol: 3/5/2003
tkritzer: 3/4/2003
tkritzer: 3/3/2003
cwells: 11/25/2002
terry: 11/20/2002
mcapotos: 8/30/2001
mcapotos: 8/23/2001
mcapotos: 7/17/2000
mcapotos: 7/14/2000
mcapotos: 7/13/2000
jlewis: 9/8/1999
terry: 8/30/1999
terry: 6/11/1999
jlewis: 6/9/1999
terry: 6/3/1999
terry: 6/2/1999
carol: 2/27/1999
carol: 5/1/1998
terry: 4/20/1998
terry: 11/4/1997
terry: 10/30/1997
terry: 10/16/1997
terry: 10/10/1997
mark: 2/12/1997
terry: 2/11/1997
mark: 8/22/1995
carol: 12/8/1994
jason: 7/13/1994
davew: 6/1/1994
mimadm: 4/18/1994
warfield: 4/15/1994

MIM 607817
*RECORD*
*FIELD* NO
607817
*FIELD* TI
*607817 VACUOLAR PROTEIN SORTING 13, YEAST, HOMOLOG OF, B; VPS13B
;;COH1 GENE; COH1;;
read moreKIAA0532
*FIELD* TX

CLONING

By sequencing clones obtained from a size-fractionated brain cDNA
library, Nagase et al. (1998) cloned COH1 (VPS13B), which they
designated KIAA0532. The 3-prime UTR contains 2 Alu repeat sequences.
RT-PCR detected COH1 expression in all tissues examined, with highest
expression in kidney.

Kolehmainen et al. (2003) identified the COH1 gene within the Cohen
syndrome (216550) critical region on chromosome 8q22. By in silico
analysis, exon prediction, and RT-PCR methods they obtained a
full-length COH1 cDNA. The longest COH1 transcript encodes a deduced
4,022-amino acid protein with a complex domain structure, including 10
predicted transmembrane domains, a potential vacuolar targeting motif,
endoplasmic reticulum retention signal in the C terminus, and 2
peroxisomal matrix protein targeting signal-2 (PTS2) consensus
sequences, one close to the N terminus and the other close to the C
terminus. COH1 shows strong homology to the Saccharomyces cerevisiae
VPS13 protein, suggesting a role for COH1 in vesicle-mediated sorting
and transport of proteins within the cell. Northern blot analysis
revealed that COH1 is widely expressed, with differential expression of
different transcripts. Transcripts of approximately 2.0 and 5.0 kb were
expressed in fetal brain, lung, liver, and kidney, and in all adult
tissues analyzed. A transcript of approximately 12 to 14 kb was
expressed in prostate, testis, ovary, and colon in the adult. Expression
was very low in adult brain tissue.

By searching databases for sequences similar to VPS13A (605978),
followed by RT-PCR of lymphoid cell line and brain RNA, Velayos-Baeza et
al. (2004) cloned COH1, which they called VPS13B. They identified 2 main
variants, variant 1A and variant 2A, and several other variants
generated by exon skipping or the use of alternative exons. Variants 1A
and 2A both contain exons 1 to 27 and 29 to 62, but variant 1A uses exon
28, while variant 2A uses an alternative exon, exon 28b. EST database
analysis indicated that there are at least 6 different 3-prime end
splice variants, 3 of which involve alternate exons 17b and 17c. Variant
1A encodes the deduced 4,022-amino acid protein, and variant 2A encodes
a deduced 3,997-amino acid protein. VPS13B shares significant similarity
with yeast Vps13 and other human VPS13 proteins only in the N and C
termini. Northern blot analysis and RT-PCR detected VPS13B expression at
variable levels in all tissues examined. Variant 2A was the predominant
transcript in all tissues examined except brain and skeletal muscle, in
which variant 1A predominated.

GENE STRUCTURE

By sequence analysis, Kolehmainen et al. (2003) determined that the COH1
gene contains 62 exons and spans a genomic region of approximately 864
kb. The COH1 gene has a complicated pattern of alternative splicing
which potentially leads to the use of 4 different termination codons and
to 3 additional in-frame, alternatively spliced forms.

Velayos-Baeza et al. (2004) determined that the COH1 gene contains 66
exons, including 4 alternative exons. The translation start codon is in
exon 2.

MAPPING

By radiation hybrid analysis, Nagase et al. (1998) mapped the COH1 gene
to chromosome 8. Kolehmainen et al. (2003) mapped the COH1 gene to
chromosome 8q22. Velayos-Baeza et al. (2004) mapped the mouse Vps13b
gene to chromosome 15B3.

MOLECULAR GENETICS

Kolehmainen et al. (2003) identified mutations in the COH1 gene in
patients with Cohen syndrome. Haplotype analysis of Finnish patients
with Cohen syndrome suggested the existence of several different
mutations. One haplotype, present in 30 of 40 (75%) disease chromosomes,
was always found to be associated with a 2-bp (CT) deletion affecting
codons 1116 and 1117 that leads to protein truncation at codon 1124
(607817.0001). Patients in 11 families were homozygous for this
mutation. It was also found in heterozygous form in 8 families, in which
the patients' other COH1 chromosome carried a different haplotype. In
only 1 of these families was a further putative mutation identified, a
leu2193-to-arg (607817.0002) missense substitution. Only 1 Finnish
family did not carry the most common haplotype and is likely to be
homozygous for an as yet unidentified COH1 mutation. The 7 mutations in
the COH1 gene identified in 5 non-Finnish patients with Cohen syndrome
by Kolehmainen et al. (2003) were predicted to result in premature
protein truncation (see, e.g., 607817.0003).

Kolehmainen et al. (2004) reported an extensive genotype-phenotype
screen in a total of 76 patients from 59 families with a provisional
diagnosis of Cohen syndrome. They found 22 different COH1 mutations, of
which 19 were novel, in probands identified by fulfilling 6 or more of
the following criteria: developmental delay, microcephaly, typical Cohen
syndrome facial gestalt, truncal obesity with slender extremities,
overly sociable behavior, joint hypermobility, high myopia and/or
retinal dystrophy, and neutropenia. By contrast, no COH1 mutations were
found in patients with a provisional diagnosis of Cohen syndrome who
were labeled 'Cohen-like.' These patients fulfilled only 5 or fewer of
the 8 criteria.

Hennies et al. (2004) described clinical and molecular findings in 20
patients with Cohen syndrome from 12 families, originating from Brazil,
Germany, Lebanon, Oman, Poland, and Turkey. All patients were homozygous
or compound heterozygous for mutations in COH1. They identified 17 novel
mutations, mostly resulting in premature termination codons. The
clinical presentation was highly variable. Developmental delay of
varying degree, early-onset myopia, joint laxity, and facial dysmorphism
were the only features present in all patients; however, retinopathy at
school age, microcephaly, and neutropenia, they concluded, are not
requisite manifestations of Cohen syndrome.

Falk et al. (2004) described 8 members from 2 large Amish kindreds with
features of Cohen syndrome but an atypical facial gestalt. Homozygosity
mapping detected linkage to the COH1 gene; sequencing of the gene
revealed that all 8 affected individuals were compound homozygous for a
1-bp insertion (9258insT; 607817.0009) and an ile2820-to-thr
substitution (I2820T; 607817.0010).

Seifert et al. (2006) studied 24 patients with Cohen syndrome from 16
families of varying ethnic backgrounds and identified 25 different
mutations in the COH1 gene, including 9 nonsense mutations, 8 frameshift
mutations, 4 verified splice site mutations, 3 larger in-frame
deletions, and 1 missense mutation. The authors noted that the vast
majority of COH1 mutations found in Cohen syndrome result in premature
termination codons.

Katzaki et al. (2007) identified pathogenic mutations in the COH1 gene
in 10 Italian patients with Cohen syndrome from 9 families. All patients
had characteristic features of the disorder, although with greater
variability than reported for Finnish patients. Heterozygous partial
COH1 gene deletions were identified in 2 different families.

Parri et al. (2010) used multiplex ligation-dependent probe
amplification (MLPA) to analyze the COH1 gene in 14 patients with Cohen
syndrome from 11 families, including 4 patients from 3 families
previously studied by Katzaki et al. (2007). Parri et al. (2010)
detected 12 different mutations, including 6 frameshift, 3 splice site,
and 2 nonsense mutations, as well as 1 complex rearrangement. Four
patients from 3 Italian families carried the same large deletion
(607817.0011) previously identified in Greek patients by Bugiani et al.
(2008). Combining these results with those from their previous study,
(Katzaki et al., 2007) yielded a total of 21 alleles with point
mutations (58%) and 15 alleles with copy number variation (42%); Parri
et al. (2010) concluded that deletions and duplications account for a
significant percentage of COH1 mutations.

*FIELD* AV
.0001
COHEN SYNDROME
VPS13B, 2-BP DEL

In 26 of 32 patients with Cohen syndrome (216550), Kolehmainen et al.
(2003) identified homozygosity or heterozygosity for a 2-bp deletion
(CT) in the COH1 gene, changing codon 1117 from cysteine to
phenylalanine and resulting in a premature termination (I1124X).

.0002
COHEN SYNDROME
VPS13B, LEU2193ARG

In a Finnish family, Kolehmainen et al. (2003) found that Cohen syndrome
(216550) was associated with compound heterozygosity for the common 2-bp
deletion (607817.0001) and a nonsense substitution, leu2193 to arg
(L2193R), in the COH1 gene.

.0003
COHEN SYNDROME
VPS13B, ARG2351TER

In a Belgian patient with Cohen syndrome (216550), Kolehmainen et al.
(2003) identified homozygosity for an arg2351-to-ter (R2351X) mutation
in exon 39 of the COH1 gene.

.0004
COHEN SYNDROME
VPS13B, ASN2993SER

In a Belgian family with Cohen syndrome (216550), Kolehmainen et al.
(2004) found homozygosity for an 8978A-G transition in exon 49 of the
COH1 gene, resulting in an asn2993-to-ser amino acid change (N2993S).

.0005
COHEN SYNDROME
VPS13B, GLU1491TER

In a British family with Cohen syndrome (216550), Kolehmainen et al.
(2004) found homozygosity for a 4471G-T transversion in exon 29 of the
COH1 gene, predicted to result in a stop mutation, glu1491 to ter
(E1491X).

.0006
COHEN SYNDROME
VPS13B, ARG971TER

In a Turkish family with Cohen syndrome (216550), Hennies et al. (2004)
identified an arg971-to-ter (R971X) mutation resulting from a 2911C-T
transition in exon 20 of the COH1 gene.

.0007
COHEN SYNDROME
VPS13B, GLY2645ASP

In an Omani family with Cohen syndrome (216550), Hennies et al. (2004)
found homozygosity for a 7934G-A transition in exon 43 of the COH1 gene
resulting in a gly2645-to-asp (G2645D) amino acid change.

.0008
COHEN SYNDROME
VPS13B, GLN3630TER

In a Turkish family with Cohen syndrome (216550), Hennies et al. (2004)
found homozygosity for a 10888C-T transition in exon 56 of the COH1 gene
resulting in a gln3630-to-ter (Q3630X) mutation.

.0009
COHEN SYNDROME
VPS13B, 1-BP INS, 9258T

In 8 members of 2 large Amish kindreds with features of Cohen syndrome
(216550) but an atypical facial gestalt, Falk et al. (2004) identified a
homozygous 1-bp insertion in exon 51 of the COH1 gene, 9258insT,
resulting in a frameshift with a premature stop codon 19 amino acids
downstream. All unaffected parents were heterozygous for this change.
Patients were also homozygous for an 8459T-C transition in exon 46 of
the COH1 gene, resulting in an ile2820-to-thr mutation (I2820T;
607817.0010).

.0010
COHEN SYNDROME
VPS13B, ILE2820THR

See 607817.0009 and Falk et al. (2004).

.0011
COHEN SYNDROME
VPS13B, EX6-16DEL

In 14 individuals with Cohen syndrome (216550) from an isolated
population on 2 small adjacent islands in the eastern part of the Greek
archipelago, Bugiani et al. (2008) identified a homozygous deletion of
exons 6 through 16 of the COH1 gene, resulting in severe truncation of
the predicted protein. Twelve of the patients belonged to a large
consanguineous kindred. The phenotype was relatively homogeneous, with
common features including moderate to severe mental retardation, slender
extremities with narrow hands and feet, joint hypermobility, and the
typical facial gestalt. Microcephaly was not as profound as reported in
Finnish patients.

In 4 patients with Cohen syndrome from 3 Italian families, including 3
patients from 2 families previously studied by Katzaki et al. (2007),
Parri et al. (2010) identified homozygosity or compound heterozygosity
(see 607817.0012 and 607817.0013) for the large deletion involving exons
6 through 16 of the VPS13B gene. Haplotype analysis of the 4 Italian
patients and 1 of the Greek patients reported by Bugiani et al. (2008)
suggested that the recurrent deletion is due to an ancestral founder
effect in the Mediterranean area.

.0012
COHEN SYNDROME
VPS13B, 1-BP DEL, 11564A

In a 6-year-old Italian boy with Cohen syndrome (216550), born of
consanguineous parents, who was originally reported by Katzaki et al.
(2007), Parri et al. (2010) identified compound heterozygosity for a
large deletion involving exons 6 through 16 of the VPS13B gene
(607817.0011) and a 1-bp deletion (11564delA), predicted to cause a
frameshift and a premature termination codon.

.0013
COHEN SYNDROME
VPS13B, EX46-50DEL

In 2 Italian sisters with Cohen syndrome (216550), originally reported
by Katzaki et al. (2007), Parri et al. (2010) identified compound
heterozygosity for 2 large deletions in the VPS13B gene: the exon 6
through 16 deletion (607817.0011) and a deletion involving exons 46
through 50. Analysis of DNA from 2 healthy sibs showed that each
unaffected sib was heterozygous for a respective deletion.

*FIELD* RF
1. Bugiani, M.; Gyftodimou, Y.; Tsimpouka, P.; Lamantea, E.; Katzaki,
E.; d'Adamo, P.; Nakou, S.; Georgoudi, N.; Grigoriadou, M.; Tsina,
E.; Kabolis, N.; Milani, D.; Pandelia, E.; Kokotas, H.; Gasparini,
P.; Giannoulia-Karantana, A.; Renieri, A.; Zeviani, M.; Petersen,
M. B.: Cohen syndrome resulting from a novel large intragenic COH1
deletion segregating in an isolated Greek island population. Am.
J. Med. Genet. 146A: 2221-2226, 2008.

2. Falk, M. J.; Feiler, H. S.; Neilson, D. E.; Maxwell, K.; Lee, J.
V.; Segall, S. K.; Robin, N. H.; Wilhelmsen, K. C.; Traskelin, A.-L.;
Kolehmainen, J.; Lehesjoki, A.-E.; Wiznitzer, M.; Warman, M. L.:
Cohen syndrome in the Ohio Amish. Am. J. Med. Genet. 128A: 23-28,
2004.

3. Hennies, H. C.; Rauch, A.; Seifert, W.; Schumi, C.; Moser, E.;
Al-Taji, E.; Tariverdian, G.; Chrzanowska, K. H.; Krajewska-Walasek,
M.; Rajab, A.; Giugliani, R.; Neumann, T. E.; Eckl, K. M.; Karbasiyan,
M.; Reis, A.; Horn, D.: Allelic heterogeneity in the COH1 gene explains
clinical variability in Cohen syndrome. Am. J. Hum. Genet. 75: 138-145,
2004.

4. Katzaki, E.; Pescucci, C.; Uliana, V.; Papa, F. T.; Ariani, F.;
Meloni, I.; Priolo, M.; Selicorni, A.; Milani, D.; Fischetto, R.;
Celle, M. E.; Grasso, R.; Dallapiccola, B.; Brancati, F.; Bordignon,
M.; Tenconi, R.; Federico, A.; Mari, F.; Renieri, A.; Longo, I.:
Clinical and molecular characterization of Italian patients affected
by Cohen syndrome. J. Hum. Genet. 52: 1011-1017, 2007. Note: Erratum:
J. Hum. Genet. 53: 285 only, 2008.

5. Kolehmainen, J.; Black, G. C. M.; Saarinen, A.; Chandler, K.; Clayton-Smith,
J.; Traskelin, A.-L.; Perveen, R.; Kivitie-Kallio, S.; Norio, R.;
Warburg, M.; Fryns, J.-P.; de la Chapelle, A.; Lehesjoki, A.-E.:
Cohen syndrome is caused by mutations in a novel gene, COH1, encoding
a transmembrane protein with a presumed role in vesicle-mediated sorting
and intracellular protein transport. Am. J. Hum. Genet. 72: 1359-1369,
2003.

6. Kolehmainen, J.; Wilkinson, R.; Lehesjoki, A.-E.; Chandler, K.;
Kivitie-Kallio, S.; Clayton-Smith, J.; Traskelin, A.-L.; Waris, L.;
Saarinen, A.; Khan, J.; Gross-Tsur, V.; Traboulsi, E. I.; Warburg,
M.; Fryns, J.-P.; Norio, R.; Black, G. C. M.; Manson, F. D. C.: Delineation
of Cohen syndrome following a large-scale genotype-phenotype screen. Am.
J. Hum. Genet. 75: 122-127, 2004.

7. Nagase, T.; Ishikawa, K.; Miyajima, N.; Tanaka, A.; Kotani, H.;
Nomura, N.; Ohara, O.: Prediction of the coding sequences of unidentified
human genes. IX. The complete sequences of 100 new cDNA clones from
brain which can code for large proteins in vitro. DNA Res. 5: 31-39,
1998.

8. Parri, V.; Katzaki, E.; Uliana, V.; Scionti, F.; Tita, R.; Artuso,
R.; Longo, I.; Boschloo, R.; Vijzelaar, R.; Selecorni, A.; Brancati,
F.; Dallapiccola, B.; and 15 others: High frequency of COH1 intragenic
deletions and duplications detected by MLPA in patients with Cohen
syndrome. Europ. J. Hum. Genet. 18: 1133-1140, 2010.

9. Seifert, W.; Holder-Espinasse, M.; Spranger, S.; Hoeltzenbein,
M.; Rossier, E.; Dollfus, H.; Lacombe, D.; Verloes, A.; Chrzanowska,
K. H.; Maegawa, G. H. B.; Chitayat, D.; Kotzot, D.; Huhle, D.; Meinecke,
P.; Albrecht, B.; Mathijssen, I.; Leheup, B.; Raile, K.; Hennies,
H. C.; Horn, D.: Mutational spectrum of COH1 and clinical heterogeneity
in Cohen syndrome. (Letter) J. Med. Genet. 43: e22, 2006. Note:
Electronic Article.

10. Velayos-Baeza, A.; Vettori, A.; Copley, R. R.; Dobson-Stone, C.;
Monaco, A. P.: Analysis of the human VPS13 gene family. Genomics 84:
536-549, 2004.

*FIELD* CN
Marla J. F. O'Neill - updated: 11/9/2010
Cassandra L. Kniffin - updated: 12/8/2008
Cassandra L. Kniffin - updated: 5/5/2008
Marla J. F. O'Neill - updated: 9/14/2006
Patricia A. Hartz - updated: 8/26/2004
Marla J. F. O'Neill - updated: 7/21/2004
Victor A. McKusick - updated: 6/30/2004

*FIELD* CD
Victor A. McKusick: 5/22/2003

*FIELD* ED
terry: 12/20/2012
wwang: 11/16/2010
terry: 11/9/2010
carol: 8/30/2010
wwang: 1/7/2009
ckniffin: 12/8/2008
wwang: 5/14/2008
ckniffin: 5/5/2008
terry: 8/6/2007
carol: 7/26/2007
wwang: 9/15/2006
terry: 9/14/2006
mgross: 8/27/2004
terry: 8/26/2004
tkritzer: 7/23/2004
terry: 7/21/2004
alopez: 7/19/2004
terry: 6/30/2004
carol: 5/22/2003