Full text data of TMEM237
TMEM237
(ALS2CR4)
[Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Transmembrane protein 237 (Amyotrophic lateral sclerosis 2 chromosomal region candidate gene 4 protein)
Transmembrane protein 237 (Amyotrophic lateral sclerosis 2 chromosomal region candidate gene 4 protein)
UniProt
Q96Q45
ID TM237_HUMAN Reviewed; 408 AA.
AC Q96Q45; B4E1R8; B4E2R8; E9PAR8; E9PBF8; E9PG24; E9PGX0; Q53TS9;
read moreAC Q53TT2; Q7Z3B6; Q8IZ18; Q8NBF8; Q96CY1;
DT 20-DEC-2005, integrated into UniProtKB/Swiss-Prot.
DT 22-FEB-2012, sequence version 2.
DT 22-JAN-2014, entry version 73.
DE RecName: Full=Transmembrane protein 237;
DE AltName: Full=Amyotrophic lateral sclerosis 2 chromosomal region candidate gene 4 protein;
GN Name=TMEM237; Synonyms=ALS2CR4;
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 3).
RX PubMed=11586298; DOI=10.1038/ng1001-166;
RA Hadano S., Hand C.K., Osuga H., Yanagisawa Y., Otomo A., Devon R.S.,
RA Miyamoto N., Showguchi-Miyata J., Okada Y., Singaraja R.,
RA Figlewicz D.A., Kwiatkowski T., Hosler B.A., Sagie T., Skaug J.,
RA Nasir J., Brown R.H. Jr., Scherer S.W., Rouleau G.A., Hayden M.R.,
RA Ikeda J.-E.;
RT "A gene encoding a putative GTPase regulator is mutated in familial
RT amyotrophic lateral sclerosis 2.";
RL Nat. Genet. 29:166-173(2001).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 2; 4 AND 5).
RC TISSUE=Trachea;
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 [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H.,
RA Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M.,
RA Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E.,
RA Kremitzki C., Oddy L., Du H., Sun H., Bradshaw-Cordum H., Ali J.,
RA Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C.,
RA Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J.,
RA Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A.,
RA Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K.,
RA Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M.,
RA Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N.,
RA Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M.,
RA Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E.,
RA Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P.,
RA Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A.,
RA Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A.,
RA Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T.,
RA Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D.,
RA Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X.,
RA McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D.,
RA Waterston R.H., Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2
RT and 4.";
RL Nature 434:724-731(2005).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Brain, and Ovary;
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 [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 272-408.
RC TISSUE=Fetal skin;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H.,
RA Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K.,
RA Ottenwaelder B., Poustka A., Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [6]
RP INVOLVEMENT IN JBTS14, SUBCELLULAR LOCATION, FUNCTION, VARIANT
RP ALA-155, AND CHARACTERIZATION OF VARIANT ALA-155.
RX PubMed=22152675; DOI=10.1016/j.ajhg.2011.11.005;
RA Huang L., Szymanska K., Jensen V.L., Janecke A.R., Innes A.M.,
RA Davis E.E., Frosk P., Li C., Willer J.R., Chodirker B.N.,
RA Greenberg C.R., McLeod D.R., Bernier F.P., Chudley A.E., Muller T.,
RA Shboul M., Logan C.V., Loucks C.M., Beaulieu C.L., Bowie R.V.,
RA Bell S.M., Adkins J., Zuniga F.I., Ross K.D., Wang J., Ban M.R.,
RA Becker C., Nurnberg P., Douglas S., Craft C.M., Akimenko M.A.,
RA Hegele R.A., Ober C., Utermann G., Bolz H.J., Bulman D.E.,
RA Katsanis N., Blacque O.E., Doherty D., Parboosingh J.S., Leroux M.R.,
RA Johnson C.A., Boycott K.M.;
RT "TMEM237 is mutated in individuals with a Joubert syndrome related
RT disorder and expands the role of the TMEM family at the ciliary
RT transition zone.";
RL Am. J. Hum. Genet. 89:713-730(2011).
CC -!- FUNCTION: Component of the transition zone in primary cilia.
CC Required for ciliogenesis.
CC -!- SUBCELLULAR LOCATION: Membrane; Multi-pass membrane protein
CC (Potential). Cell projection, cilium. Note=Localizes at the
CC proximal region of primary cilia were observed, consistent with
CC localization to the transition zone. Anchored to the transition
CC zone by RPGRIP1L.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=5;
CC Name=1;
CC IsoId=Q96Q45-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q96Q45-2; Sequence=VSP_016628;
CC Name=3;
CC IsoId=Q96Q45-3; Sequence=VSP_042381;
CC Name=4;
CC IsoId=Q96Q45-4; Sequence=VSP_042382;
CC Name=5;
CC IsoId=Q96Q45-5; Sequence=VSP_042383;
CC -!- DISEASE: Joubert syndrome 14 (JBTS14) [MIM:614424]: An autosomal
CC recessive disorder characterized by severe mental retardation,
CC hypotonia, breathing abnormalities in infancy, and dysmorphic
CC facial features. Neuroradiologically, it is characterized by
CC cerebellar vermian hypoplasia/aplasia, thickened and reoriented
CC superior cerebellar peduncles, and an abnormally large
CC interpeduncular fossa, giving the appearance of a molar tooth on
CC transaxial slices (molar tooth sign). Additional variable features
CC include renal disease, abnormal eye movements, and postaxial
CC polydactyly. Note=The disease is caused by mutations affecting the
CC gene represented in this entry.
CC -!- SIMILARITY: Belongs to the TMEM237 family.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAY14694.1; Type=Erroneous gene model prediction;
CC Sequence=AAY15056.1; Type=Erroneous gene model prediction;
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DR EMBL; AB053301; BAB69011.1; -; mRNA.
DR EMBL; AK090601; BAC03487.1; -; mRNA.
DR EMBL; AK303954; BAG64880.1; -; mRNA.
DR EMBL; AK304395; BAG65230.1; -; mRNA.
DR EMBL; AC007279; AAY15056.1; ALT_SEQ; Genomic_DNA.
DR EMBL; AC007282; AAY14694.1; ALT_SEQ; Genomic_DNA.
DR EMBL; BC013730; AAH13730.1; -; mRNA.
DR EMBL; BC029611; AAH29611.1; -; mRNA.
DR EMBL; BX538000; CAD97955.1; -; mRNA.
DR RefSeq; NP_001037850.1; NM_001044385.2.
DR RefSeq; NP_689601.2; NM_152388.3.
DR RefSeq; XP_005246842.1; XM_005246785.1.
DR UniGene; Hs.12319; -.
DR ProteinModelPortal; Q96Q45; -.
DR IntAct; Q96Q45; 2.
DR STRING; 9606.ENSP00000380113; -.
DR PhosphoSite; Q96Q45; -.
DR DMDM; 74732666; -.
DR PaxDb; Q96Q45; -.
DR PRIDE; Q96Q45; -.
DR DNASU; 65062; -.
DR Ensembl; ENST00000409444; ENSP00000387203; ENSG00000155755.
DR Ensembl; ENST00000409883; ENSP00000386264; ENSG00000155755.
DR GeneID; 65062; -.
DR KEGG; hsa:65062; -.
DR UCSC; uc021vvf.2; human.
DR CTD; 65062; -.
DR GeneCards; GC02M202484; -.
DR HGNC; HGNC:14432; TMEM237.
DR MIM; 614423; gene.
DR MIM; 614424; phenotype.
DR neXtProt; NX_Q96Q45; -.
DR Orphanet; 475; Joubert syndrome.
DR Orphanet; 220493; Joubert syndrome with ocular defect.
DR Orphanet; 2318; Joubert syndrome with oculorenal defect.
DR Orphanet; 220497; Joubert syndrome with renal defect.
DR PharmGKB; PA24745; -.
DR eggNOG; NOG71278; -.
DR HOGENOM; HOG000033887; -.
DR HOVERGEN; HBG060391; -.
DR InParanoid; Q96Q45; -.
DR OMA; SWLFLSY; -.
DR OrthoDB; EOG7T4MKS; -.
DR GenomeRNAi; 65062; -.
DR NextBio; 67248; -.
DR PRO; PR:Q96Q45; -.
DR ArrayExpress; Q96Q45; -.
DR Bgee; Q96Q45; -.
DR CleanEx; HS_ALS2CR4; -.
DR Genevestigator; Q96Q45; -.
DR GO; GO:0035869; C:ciliary transition zone; IDA:UniProtKB.
DR GO; GO:0016021; C:integral to membrane; IEA:UniProtKB-KW.
DR GO; GO:0042384; P:cilium assembly; IMP:UniProtKB.
DR GO; GO:0030111; P:regulation of Wnt receptor signaling pathway; IMP:UniProtKB.
PE 1: Evidence at protein level;
KW Alternative splicing; Cell projection; Ciliopathy; Cilium;
KW Cilium biogenesis/degradation; Complete proteome; Joubert syndrome;
KW Membrane; Polymorphism; Reference proteome; Transmembrane;
KW Transmembrane helix.
FT CHAIN 1 408 Transmembrane protein 237.
FT /FTId=PRO_0000076169.
FT TRANSMEM 227 247 Helical; (Potential).
FT TRANSMEM 268 288 Helical; (Potential).
FT TRANSMEM 303 323 Helical; (Potential).
FT TRANSMEM 358 378 Helical; (Potential).
FT VAR_SEQ 1 14 MRTDSGARLEEGHL -> MGKNPV (in isoform 2).
FT /FTId=VSP_016628.
FT VAR_SEQ 1 14 MRTDSGARLEEGHL -> MTHCACARDRAREGWGARCLGAR
FT RPPRPAKRRMGKNPV (in isoform 3).
FT /FTId=VSP_042381.
FT VAR_SEQ 36 130 Missing (in isoform 4).
FT /FTId=VSP_042382.
FT VAR_SEQ 132 132 K -> KRPYYR (in isoform 5).
FT /FTId=VSP_042383.
FT VARIANT 155 155 D -> A (found at heterozygosity in a
FT patient with Bardet-Biedl syndrome also
FT carrying BBS6 mutation A-57 in MKKS;
FT hypomorphic variant).
FT /FTId=VAR_067019.
FT CONFLICT 20 20 L -> I (in Ref. 4; AAH29611).
FT CONFLICT 118 118 P -> Q (in Ref. 4; AAH29611).
FT CONFLICT 158 158 T -> A (in Ref. 2; BAG64880).
FT CONFLICT 215 215 R -> I (in Ref. 4; AAH29611).
FT CONFLICT 261 261 L -> I (in Ref. 4; AAH29611).
SQ SEQUENCE 408 AA; 45526 MW; 5FF78A331490D190 CRC64;
MRTDSGARLE EGHLRPPRAL PPVPSQDDIP LSRPKKKKPR TKNTPASASL EGLAQTAGRR
PSEGNEPSTK ELKEHPEAPV QRRQKKTRLP LELETSSTQK KSSSSSLLRN ENGIDAEPAE
EAVIQKPRRK TKKTQPAELQ YANELGVEDE DIITDEQTTV EQQSVFTAPT GISQPVGKVF
VEKSRRFQAA DRSELIKTTE NIDVSMDVKP SWTTRDVALT VHRAFRMIGL FSHGFLAGCA
VWNIVVIYVL AGDQLSNLSN LLQQYKTLAY PFQSLLYLLL ALSTISAFDR IDFAKISVAI
RNFLALDPTA LASFLYFTAL ILSLSQQMTS DRIHLYTPSS VNGSLWEAGI EEQILQPWIV
VNLVVALLVG LSWLFLSYRP GMDLSEELMF SSEVEEYPDK EKEIKASS
//
ID TM237_HUMAN Reviewed; 408 AA.
AC Q96Q45; B4E1R8; B4E2R8; E9PAR8; E9PBF8; E9PG24; E9PGX0; Q53TS9;
read moreAC Q53TT2; Q7Z3B6; Q8IZ18; Q8NBF8; Q96CY1;
DT 20-DEC-2005, integrated into UniProtKB/Swiss-Prot.
DT 22-FEB-2012, sequence version 2.
DT 22-JAN-2014, entry version 73.
DE RecName: Full=Transmembrane protein 237;
DE AltName: Full=Amyotrophic lateral sclerosis 2 chromosomal region candidate gene 4 protein;
GN Name=TMEM237; Synonyms=ALS2CR4;
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 3).
RX PubMed=11586298; DOI=10.1038/ng1001-166;
RA Hadano S., Hand C.K., Osuga H., Yanagisawa Y., Otomo A., Devon R.S.,
RA Miyamoto N., Showguchi-Miyata J., Okada Y., Singaraja R.,
RA Figlewicz D.A., Kwiatkowski T., Hosler B.A., Sagie T., Skaug J.,
RA Nasir J., Brown R.H. Jr., Scherer S.W., Rouleau G.A., Hayden M.R.,
RA Ikeda J.-E.;
RT "A gene encoding a putative GTPase regulator is mutated in familial
RT amyotrophic lateral sclerosis 2.";
RL Nat. Genet. 29:166-173(2001).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 2; 4 AND 5).
RC TISSUE=Trachea;
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 [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H.,
RA Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M.,
RA Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E.,
RA Kremitzki C., Oddy L., Du H., Sun H., Bradshaw-Cordum H., Ali J.,
RA Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C.,
RA Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J.,
RA Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A.,
RA Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K.,
RA Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M.,
RA Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N.,
RA Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M.,
RA Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E.,
RA Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P.,
RA Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A.,
RA Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A.,
RA Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T.,
RA Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D.,
RA Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X.,
RA McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D.,
RA Waterston R.H., Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2
RT and 4.";
RL Nature 434:724-731(2005).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Brain, and Ovary;
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 [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 272-408.
RC TISSUE=Fetal skin;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H.,
RA Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K.,
RA Ottenwaelder B., Poustka A., Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [6]
RP INVOLVEMENT IN JBTS14, SUBCELLULAR LOCATION, FUNCTION, VARIANT
RP ALA-155, AND CHARACTERIZATION OF VARIANT ALA-155.
RX PubMed=22152675; DOI=10.1016/j.ajhg.2011.11.005;
RA Huang L., Szymanska K., Jensen V.L., Janecke A.R., Innes A.M.,
RA Davis E.E., Frosk P., Li C., Willer J.R., Chodirker B.N.,
RA Greenberg C.R., McLeod D.R., Bernier F.P., Chudley A.E., Muller T.,
RA Shboul M., Logan C.V., Loucks C.M., Beaulieu C.L., Bowie R.V.,
RA Bell S.M., Adkins J., Zuniga F.I., Ross K.D., Wang J., Ban M.R.,
RA Becker C., Nurnberg P., Douglas S., Craft C.M., Akimenko M.A.,
RA Hegele R.A., Ober C., Utermann G., Bolz H.J., Bulman D.E.,
RA Katsanis N., Blacque O.E., Doherty D., Parboosingh J.S., Leroux M.R.,
RA Johnson C.A., Boycott K.M.;
RT "TMEM237 is mutated in individuals with a Joubert syndrome related
RT disorder and expands the role of the TMEM family at the ciliary
RT transition zone.";
RL Am. J. Hum. Genet. 89:713-730(2011).
CC -!- FUNCTION: Component of the transition zone in primary cilia.
CC Required for ciliogenesis.
CC -!- SUBCELLULAR LOCATION: Membrane; Multi-pass membrane protein
CC (Potential). Cell projection, cilium. Note=Localizes at the
CC proximal region of primary cilia were observed, consistent with
CC localization to the transition zone. Anchored to the transition
CC zone by RPGRIP1L.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=5;
CC Name=1;
CC IsoId=Q96Q45-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q96Q45-2; Sequence=VSP_016628;
CC Name=3;
CC IsoId=Q96Q45-3; Sequence=VSP_042381;
CC Name=4;
CC IsoId=Q96Q45-4; Sequence=VSP_042382;
CC Name=5;
CC IsoId=Q96Q45-5; Sequence=VSP_042383;
CC -!- DISEASE: Joubert syndrome 14 (JBTS14) [MIM:614424]: An autosomal
CC recessive disorder characterized by severe mental retardation,
CC hypotonia, breathing abnormalities in infancy, and dysmorphic
CC facial features. Neuroradiologically, it is characterized by
CC cerebellar vermian hypoplasia/aplasia, thickened and reoriented
CC superior cerebellar peduncles, and an abnormally large
CC interpeduncular fossa, giving the appearance of a molar tooth on
CC transaxial slices (molar tooth sign). Additional variable features
CC include renal disease, abnormal eye movements, and postaxial
CC polydactyly. Note=The disease is caused by mutations affecting the
CC gene represented in this entry.
CC -!- SIMILARITY: Belongs to the TMEM237 family.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAY14694.1; Type=Erroneous gene model prediction;
CC Sequence=AAY15056.1; Type=Erroneous gene model prediction;
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; AB053301; BAB69011.1; -; mRNA.
DR EMBL; AK090601; BAC03487.1; -; mRNA.
DR EMBL; AK303954; BAG64880.1; -; mRNA.
DR EMBL; AK304395; BAG65230.1; -; mRNA.
DR EMBL; AC007279; AAY15056.1; ALT_SEQ; Genomic_DNA.
DR EMBL; AC007282; AAY14694.1; ALT_SEQ; Genomic_DNA.
DR EMBL; BC013730; AAH13730.1; -; mRNA.
DR EMBL; BC029611; AAH29611.1; -; mRNA.
DR EMBL; BX538000; CAD97955.1; -; mRNA.
DR RefSeq; NP_001037850.1; NM_001044385.2.
DR RefSeq; NP_689601.2; NM_152388.3.
DR RefSeq; XP_005246842.1; XM_005246785.1.
DR UniGene; Hs.12319; -.
DR ProteinModelPortal; Q96Q45; -.
DR IntAct; Q96Q45; 2.
DR STRING; 9606.ENSP00000380113; -.
DR PhosphoSite; Q96Q45; -.
DR DMDM; 74732666; -.
DR PaxDb; Q96Q45; -.
DR PRIDE; Q96Q45; -.
DR DNASU; 65062; -.
DR Ensembl; ENST00000409444; ENSP00000387203; ENSG00000155755.
DR Ensembl; ENST00000409883; ENSP00000386264; ENSG00000155755.
DR GeneID; 65062; -.
DR KEGG; hsa:65062; -.
DR UCSC; uc021vvf.2; human.
DR CTD; 65062; -.
DR GeneCards; GC02M202484; -.
DR HGNC; HGNC:14432; TMEM237.
DR MIM; 614423; gene.
DR MIM; 614424; phenotype.
DR neXtProt; NX_Q96Q45; -.
DR Orphanet; 475; Joubert syndrome.
DR Orphanet; 220493; Joubert syndrome with ocular defect.
DR Orphanet; 2318; Joubert syndrome with oculorenal defect.
DR Orphanet; 220497; Joubert syndrome with renal defect.
DR PharmGKB; PA24745; -.
DR eggNOG; NOG71278; -.
DR HOGENOM; HOG000033887; -.
DR HOVERGEN; HBG060391; -.
DR InParanoid; Q96Q45; -.
DR OMA; SWLFLSY; -.
DR OrthoDB; EOG7T4MKS; -.
DR GenomeRNAi; 65062; -.
DR NextBio; 67248; -.
DR PRO; PR:Q96Q45; -.
DR ArrayExpress; Q96Q45; -.
DR Bgee; Q96Q45; -.
DR CleanEx; HS_ALS2CR4; -.
DR Genevestigator; Q96Q45; -.
DR GO; GO:0035869; C:ciliary transition zone; IDA:UniProtKB.
DR GO; GO:0016021; C:integral to membrane; IEA:UniProtKB-KW.
DR GO; GO:0042384; P:cilium assembly; IMP:UniProtKB.
DR GO; GO:0030111; P:regulation of Wnt receptor signaling pathway; IMP:UniProtKB.
PE 1: Evidence at protein level;
KW Alternative splicing; Cell projection; Ciliopathy; Cilium;
KW Cilium biogenesis/degradation; Complete proteome; Joubert syndrome;
KW Membrane; Polymorphism; Reference proteome; Transmembrane;
KW Transmembrane helix.
FT CHAIN 1 408 Transmembrane protein 237.
FT /FTId=PRO_0000076169.
FT TRANSMEM 227 247 Helical; (Potential).
FT TRANSMEM 268 288 Helical; (Potential).
FT TRANSMEM 303 323 Helical; (Potential).
FT TRANSMEM 358 378 Helical; (Potential).
FT VAR_SEQ 1 14 MRTDSGARLEEGHL -> MGKNPV (in isoform 2).
FT /FTId=VSP_016628.
FT VAR_SEQ 1 14 MRTDSGARLEEGHL -> MTHCACARDRAREGWGARCLGAR
FT RPPRPAKRRMGKNPV (in isoform 3).
FT /FTId=VSP_042381.
FT VAR_SEQ 36 130 Missing (in isoform 4).
FT /FTId=VSP_042382.
FT VAR_SEQ 132 132 K -> KRPYYR (in isoform 5).
FT /FTId=VSP_042383.
FT VARIANT 155 155 D -> A (found at heterozygosity in a
FT patient with Bardet-Biedl syndrome also
FT carrying BBS6 mutation A-57 in MKKS;
FT hypomorphic variant).
FT /FTId=VAR_067019.
FT CONFLICT 20 20 L -> I (in Ref. 4; AAH29611).
FT CONFLICT 118 118 P -> Q (in Ref. 4; AAH29611).
FT CONFLICT 158 158 T -> A (in Ref. 2; BAG64880).
FT CONFLICT 215 215 R -> I (in Ref. 4; AAH29611).
FT CONFLICT 261 261 L -> I (in Ref. 4; AAH29611).
SQ SEQUENCE 408 AA; 45526 MW; 5FF78A331490D190 CRC64;
MRTDSGARLE EGHLRPPRAL PPVPSQDDIP LSRPKKKKPR TKNTPASASL EGLAQTAGRR
PSEGNEPSTK ELKEHPEAPV QRRQKKTRLP LELETSSTQK KSSSSSLLRN ENGIDAEPAE
EAVIQKPRRK TKKTQPAELQ YANELGVEDE DIITDEQTTV EQQSVFTAPT GISQPVGKVF
VEKSRRFQAA DRSELIKTTE NIDVSMDVKP SWTTRDVALT VHRAFRMIGL FSHGFLAGCA
VWNIVVIYVL AGDQLSNLSN LLQQYKTLAY PFQSLLYLLL ALSTISAFDR IDFAKISVAI
RNFLALDPTA LASFLYFTAL ILSLSQQMTS DRIHLYTPSS VNGSLWEAGI EEQILQPWIV
VNLVVALLVG LSWLFLSYRP GMDLSEELMF SSEVEEYPDK EKEIKASS
//
MIM
614423
*RECORD*
*FIELD* NO
614423
*FIELD* TI
*614423 TRANSMEMBRANE PROTEIN 237; TMEM237
;;ALS2 CHROMOSOME REGION GENE 4; ALS2CR4
read more*FIELD* TX
DESCRIPTION
TMEM237 is a tetraspanin protein localized to the ciliary transition
zone that is predicted to function with other transition zone proteins
in canonical and noncanonical Wnt (see 164820) signaling (Huang et al.,
2011).
CLONING
Huang et al. (2011) identified 2 TMEM237 splice variants that include
either exon 1 or exon 2 and are translated into 2 different protein
isoforms. Transcript-1 contains exon 1 and encodes a deduced 408-amino
acid protein, designated isoform A, that has a long N-terminal domain,
followed by 4 transmembrane domains and a short C-terminal tail. Both
the N- and C-terminal domains are intracellular. The N-terminal domain
and the intracellular loops between the transmembrane helices contain
short repetitive motifs of basic (arg and/or lys) and acidic (asp and/or
glu) residues that are highly conserved in metazoans. Immunocytochemical
staining of polarized ciliated mouse inner medullary collecting duct
(IMCD3) cells revealed that Tmem237 localized to the transition zone at
the proximal region of primary cilia.
Zuniga and Craft (2010) cloned mouse Tmem237, which they called Als2cr4,
and identified variants encoding 2 protein isoforms that differ only at
the extreme N terminus. The deduced 403-amino acid protein encoded by
Als2cr4 transcript-2 has a calculated molecular mass of about 45 kD and
shares 81% and 82% identity with isoforms A and B of human ALS2CR4,
respectively. Mouse Als2cr4 has a long N-terminal domain containing a
tetratricopeptide motif, followed by 4 transmembrane segments and a
short C-terminal tail. Zuniga and Craft (2010) noted that previous in
situ hybridization and gene expression profiles revealed high Als2cr4
expression in eye, hippocampus, cerebellum, and olfactory bulb. By
immunohistochemical analysis of retina, Zuniga and Craft (2010) found
Als2cr4 enriched in retina and localized to photoreceptor outer
segments, ciliary complex, and horizontal cells in the outer plexiform
layer. Immunoelectron microscopy verified Als2cr4 expression in the
discs of photoreceptor outer segments.
GENE FUNCTION
By yeast 2-hybrid analysis of mouse retina, Zuniga and Craft (2010)
found that Als2cr4 interacted with Arr4 (ARR3; 301770).
Immunoprecipitation analysis of light-adapted mouse retinas showed that
Als2cr4 associated with cytoskeletal components. Als2cr4 interacted
directly with myosin Va (MYO5A; 160777), myosin VI (MYO6; 600970), and
Arr3.
Huang et al. (2011) found that knockdown of Tmem237 in IMCD3 cells via
small interfering RNA impaired ciliogenesis and caused mislocalization
of RhoA (165390) to peripheral regions of the basal body and to
basolateral cell-cell contacts. Similarly, fibroblasts from a patient
with Joubert syndrome-14 (JBTS14; 614424) and a null mutation in TMEM237
(R18X; 614423.0001) showed deregulation of canonical and noncanonical
Wnt signaling and mislocalization of RHOA. Morpholino-mediated knockdown
of Tmem237 in zebrafish caused gastrulation defects consistent with
ciliary dysfunction that were similar to defects resulting from
knockdown of other transition zone proteins, including Mks3 (TMEM67;
609884) and Tmem216 (613277). These defects in zebrafish were partially
reversed by expression of human TMEM237, MKS3, or TMEM216. In both IMCD3
cells and C. elegans, transition zone localization of Tmem237 was
dependent upon other transition zone proteins. Huang et al. (2011)
hypothesized that TMEM237, TMEM216, and MKS3 function as a module to
regulate ciliogenesis and WNT signaling.
GENE STRUCTURE
Huang et al. (2011) determined that the TMEM237 gene contains 14 exons
and spans 23 kb.
MAPPING
Zuniga and Craft (2010) stated that the human TMEM237 gene maps to
chromosome 2q33.2 and that the mouse ortholog maps to chromosome 1.
MOLECULAR GENETICS
By homozygosity mapping followed by candidate gene analysis in 10
related Canadian Hutterite families with Joubert syndrome-14 (JBTS14;
614424), Huang et al. (2011) identified a homozygous truncating mutation
in the TMEM237 gene (R18X; 614423.0001). Homozygous or compound
heterozygous mutations were also found in 3 additional families with the
disorder (614423.0002-614423.0005). All the mutations were predicted to
result in a null allele. Protein extracts from patient cells showed
perturbation of the noncanonical WNT pathway, with constitutive
phosphorylation and hyperactivation of DVL1 (601365) and an increase in
CTNNB1 (116806) levels. There was also an increase in RHOA signaling.
The phenotype was characterized by severe mental retardation, abnormal
breathing pattern in infancy, molar tooth sign (MTS) on brain imaging,
renal cysts, abnormal eye movements, and early death in many patients.
*FIELD* AV
.0001
JOUBERT SYNDROME 14
TMEM237, ARG18TER (dbSNP rs199469707)
In affected members of 10 related Canadian Hutterite families with
Joubert syndrome-14 (JBTS14; 614424) (Boycott et al., 2007), Huang et
al. (2011) identified a homozygous 52C-T transition in the TMEM237 gene,
resulting in an arg18-to-ter (R18X) substitution. Screening of normal
Hutterite controls showed a carrier frequency of 6% for this mutation.
The mutation was not found in over 105 northern European controls.
TMEM237 transcript levels were reduced by 99.6% in patient fibroblasts,
and these cells showed defective ciliogenesis and pairing of centrioles
compared to control cells.
Chong et al. (2012) identified a carrier frequency for this mutation of
0.080 (1 in 12.5) among Schmiedeleut (S-leut) Hutterites in the United
States. This mutation is private to the Hutterite population.
.0002
JOUBERT SYNDROME 14
TMEM237, IVS9DS, G-T, +1
In affected members of a consanguineous Austrian family with Joubert
syndrome-14 (614424) (Janecke et al., 2004), Huang et al. (2011)
identified a homozygous G-to-T transversion in intron 9 of the TMEM237
gene (677+1G-T). RT-PCR analysis and sequencing of a patient's
fibroblasts showed 2 aberrant transcripts: one resulting in the deletion
of 65 amino acids and the insertion of a serine residue, and another
resulting in the skipping of exon 9 and premature termination. TMEM237
transcript levels were reduced by 98.4% in patient fibroblasts, and
these cells showed defective ciliogenesis and pairing of centrioles
compared to control cells.
.0003
JOUBERT SYNDROME 14
TMEM237, 1-BP DUP, 1066C
In a Jordanian child, born of consanguineous parents, with JBTS14
(614424), Huang et al. (2011) identified a homozygous 1-bp duplication
(1066dupC) in exon 13 of the TMEM237 gene, predicted to result in a
frameshift and premature termination. The mutation was not found in over
105 Jordanian controls.
.0004
JOUBERT SYNDROME 14
TMEM237, GLN26TER
In a child of European and Spanish descent with JBTS14 (614424), Huang
et al. (2011) identified compound heterozygosity for 2 mutations in the
TMEM237 gene: a maternally inherited 76C-T transition, resulting in a
gln26-to-ter (Q26X) substitution, and a paternally inherited G-to-T
transversion in intron 11 (943+1G-T; 614423.0005), resulting in an
in-frame deletion of 56 amino acids (exons 11 and 12). The mutations
were not found in over 105 controls.
.0005
JOUBERT SYNDROME 14
TMEM237, IVS11DS, G-T, +1
See 614423.0004 and Huang et al. (2011).
*FIELD* RF
1. Boycott, K. M.; Parboosingh, J. S.; Scott, J. N.; McLeod, D. R.;
Greenberg, C. R.; Fujiwara, T. M.; Mah, J. K.; Midgley, J.; Wade,
A.; Bernier, F. P.; Chodirker, B. N.; Bunge, M.; Innes, A. M.: Meckel
syndrome in the Hutterite population is actually a Joubert-related
cerebello-oculo-renal syndrome. Am. J. Med. Genet. 143A: 1715-1725,
2007.
2. Chong, J. X.; Ouwenga, R.; Anderson, R. L.; Waggoner, D. J.; Ober,
C.: A population-based study of autosomal-recessive disease-causing
mutations in a founder population. Am. J. Hum. Genet. 91: 608-620,
2012.
3. Huang, L.; Szymanska, K.; Jensen, V. L.; Janecke, A. R.; Innes,
A. M.; Davis, E. E.; Frosk, P.; Li, C.; Willer, J. R.; Chodirker,
B. N.; Greenberg, C. R.; McLeod, D. R.; and 31 others: TMEM237
is mutated in individuals with a Joubert syndrome related disorder
and expands the role of the TMEM family at the ciliary transition
zone. Am. J. Hum. Genet. 89: 713-730, 2011.
4. Janecke, A. R.; Muller, T.; Gassner, I.; Kreczy, A.; Schmid, E.;
Kronenberg, F.; Utermann, B.; Utermann, G.: Joubert-like syndrome
unlinked to known candidate loci. J. Pediat. 144: 264-269, 2004.
5. Zuniga, F. I.; Craft, C. M.: Deciphering the structure and function
of Als2cr4 in the mouse retina. Invest. Ophthal. Vis. Sci. 51: 4407-4415,
2010.
*FIELD* CN
Ada Hamosh - updated: 2/11/2013
Cassandra L. Kniffin - updated: 1/11/2012
*FIELD* CD
Patricia A. Hartz: 1/10/2012
*FIELD* ED
carol: 09/06/2013
alopez: 2/11/2013
mgross: 1/19/2012
joanna: 1/18/2012
carol: 1/11/2012
ckniffin: 1/11/2012
mgross: 1/10/2012
*RECORD*
*FIELD* NO
614423
*FIELD* TI
*614423 TRANSMEMBRANE PROTEIN 237; TMEM237
;;ALS2 CHROMOSOME REGION GENE 4; ALS2CR4
read more*FIELD* TX
DESCRIPTION
TMEM237 is a tetraspanin protein localized to the ciliary transition
zone that is predicted to function with other transition zone proteins
in canonical and noncanonical Wnt (see 164820) signaling (Huang et al.,
2011).
CLONING
Huang et al. (2011) identified 2 TMEM237 splice variants that include
either exon 1 or exon 2 and are translated into 2 different protein
isoforms. Transcript-1 contains exon 1 and encodes a deduced 408-amino
acid protein, designated isoform A, that has a long N-terminal domain,
followed by 4 transmembrane domains and a short C-terminal tail. Both
the N- and C-terminal domains are intracellular. The N-terminal domain
and the intracellular loops between the transmembrane helices contain
short repetitive motifs of basic (arg and/or lys) and acidic (asp and/or
glu) residues that are highly conserved in metazoans. Immunocytochemical
staining of polarized ciliated mouse inner medullary collecting duct
(IMCD3) cells revealed that Tmem237 localized to the transition zone at
the proximal region of primary cilia.
Zuniga and Craft (2010) cloned mouse Tmem237, which they called Als2cr4,
and identified variants encoding 2 protein isoforms that differ only at
the extreme N terminus. The deduced 403-amino acid protein encoded by
Als2cr4 transcript-2 has a calculated molecular mass of about 45 kD and
shares 81% and 82% identity with isoforms A and B of human ALS2CR4,
respectively. Mouse Als2cr4 has a long N-terminal domain containing a
tetratricopeptide motif, followed by 4 transmembrane segments and a
short C-terminal tail. Zuniga and Craft (2010) noted that previous in
situ hybridization and gene expression profiles revealed high Als2cr4
expression in eye, hippocampus, cerebellum, and olfactory bulb. By
immunohistochemical analysis of retina, Zuniga and Craft (2010) found
Als2cr4 enriched in retina and localized to photoreceptor outer
segments, ciliary complex, and horizontal cells in the outer plexiform
layer. Immunoelectron microscopy verified Als2cr4 expression in the
discs of photoreceptor outer segments.
GENE FUNCTION
By yeast 2-hybrid analysis of mouse retina, Zuniga and Craft (2010)
found that Als2cr4 interacted with Arr4 (ARR3; 301770).
Immunoprecipitation analysis of light-adapted mouse retinas showed that
Als2cr4 associated with cytoskeletal components. Als2cr4 interacted
directly with myosin Va (MYO5A; 160777), myosin VI (MYO6; 600970), and
Arr3.
Huang et al. (2011) found that knockdown of Tmem237 in IMCD3 cells via
small interfering RNA impaired ciliogenesis and caused mislocalization
of RhoA (165390) to peripheral regions of the basal body and to
basolateral cell-cell contacts. Similarly, fibroblasts from a patient
with Joubert syndrome-14 (JBTS14; 614424) and a null mutation in TMEM237
(R18X; 614423.0001) showed deregulation of canonical and noncanonical
Wnt signaling and mislocalization of RHOA. Morpholino-mediated knockdown
of Tmem237 in zebrafish caused gastrulation defects consistent with
ciliary dysfunction that were similar to defects resulting from
knockdown of other transition zone proteins, including Mks3 (TMEM67;
609884) and Tmem216 (613277). These defects in zebrafish were partially
reversed by expression of human TMEM237, MKS3, or TMEM216. In both IMCD3
cells and C. elegans, transition zone localization of Tmem237 was
dependent upon other transition zone proteins. Huang et al. (2011)
hypothesized that TMEM237, TMEM216, and MKS3 function as a module to
regulate ciliogenesis and WNT signaling.
GENE STRUCTURE
Huang et al. (2011) determined that the TMEM237 gene contains 14 exons
and spans 23 kb.
MAPPING
Zuniga and Craft (2010) stated that the human TMEM237 gene maps to
chromosome 2q33.2 and that the mouse ortholog maps to chromosome 1.
MOLECULAR GENETICS
By homozygosity mapping followed by candidate gene analysis in 10
related Canadian Hutterite families with Joubert syndrome-14 (JBTS14;
614424), Huang et al. (2011) identified a homozygous truncating mutation
in the TMEM237 gene (R18X; 614423.0001). Homozygous or compound
heterozygous mutations were also found in 3 additional families with the
disorder (614423.0002-614423.0005). All the mutations were predicted to
result in a null allele. Protein extracts from patient cells showed
perturbation of the noncanonical WNT pathway, with constitutive
phosphorylation and hyperactivation of DVL1 (601365) and an increase in
CTNNB1 (116806) levels. There was also an increase in RHOA signaling.
The phenotype was characterized by severe mental retardation, abnormal
breathing pattern in infancy, molar tooth sign (MTS) on brain imaging,
renal cysts, abnormal eye movements, and early death in many patients.
*FIELD* AV
.0001
JOUBERT SYNDROME 14
TMEM237, ARG18TER (dbSNP rs199469707)
In affected members of 10 related Canadian Hutterite families with
Joubert syndrome-14 (JBTS14; 614424) (Boycott et al., 2007), Huang et
al. (2011) identified a homozygous 52C-T transition in the TMEM237 gene,
resulting in an arg18-to-ter (R18X) substitution. Screening of normal
Hutterite controls showed a carrier frequency of 6% for this mutation.
The mutation was not found in over 105 northern European controls.
TMEM237 transcript levels were reduced by 99.6% in patient fibroblasts,
and these cells showed defective ciliogenesis and pairing of centrioles
compared to control cells.
Chong et al. (2012) identified a carrier frequency for this mutation of
0.080 (1 in 12.5) among Schmiedeleut (S-leut) Hutterites in the United
States. This mutation is private to the Hutterite population.
.0002
JOUBERT SYNDROME 14
TMEM237, IVS9DS, G-T, +1
In affected members of a consanguineous Austrian family with Joubert
syndrome-14 (614424) (Janecke et al., 2004), Huang et al. (2011)
identified a homozygous G-to-T transversion in intron 9 of the TMEM237
gene (677+1G-T). RT-PCR analysis and sequencing of a patient's
fibroblasts showed 2 aberrant transcripts: one resulting in the deletion
of 65 amino acids and the insertion of a serine residue, and another
resulting in the skipping of exon 9 and premature termination. TMEM237
transcript levels were reduced by 98.4% in patient fibroblasts, and
these cells showed defective ciliogenesis and pairing of centrioles
compared to control cells.
.0003
JOUBERT SYNDROME 14
TMEM237, 1-BP DUP, 1066C
In a Jordanian child, born of consanguineous parents, with JBTS14
(614424), Huang et al. (2011) identified a homozygous 1-bp duplication
(1066dupC) in exon 13 of the TMEM237 gene, predicted to result in a
frameshift and premature termination. The mutation was not found in over
105 Jordanian controls.
.0004
JOUBERT SYNDROME 14
TMEM237, GLN26TER
In a child of European and Spanish descent with JBTS14 (614424), Huang
et al. (2011) identified compound heterozygosity for 2 mutations in the
TMEM237 gene: a maternally inherited 76C-T transition, resulting in a
gln26-to-ter (Q26X) substitution, and a paternally inherited G-to-T
transversion in intron 11 (943+1G-T; 614423.0005), resulting in an
in-frame deletion of 56 amino acids (exons 11 and 12). The mutations
were not found in over 105 controls.
.0005
JOUBERT SYNDROME 14
TMEM237, IVS11DS, G-T, +1
See 614423.0004 and Huang et al. (2011).
*FIELD* RF
1. Boycott, K. M.; Parboosingh, J. S.; Scott, J. N.; McLeod, D. R.;
Greenberg, C. R.; Fujiwara, T. M.; Mah, J. K.; Midgley, J.; Wade,
A.; Bernier, F. P.; Chodirker, B. N.; Bunge, M.; Innes, A. M.: Meckel
syndrome in the Hutterite population is actually a Joubert-related
cerebello-oculo-renal syndrome. Am. J. Med. Genet. 143A: 1715-1725,
2007.
2. Chong, J. X.; Ouwenga, R.; Anderson, R. L.; Waggoner, D. J.; Ober,
C.: A population-based study of autosomal-recessive disease-causing
mutations in a founder population. Am. J. Hum. Genet. 91: 608-620,
2012.
3. Huang, L.; Szymanska, K.; Jensen, V. L.; Janecke, A. R.; Innes,
A. M.; Davis, E. E.; Frosk, P.; Li, C.; Willer, J. R.; Chodirker,
B. N.; Greenberg, C. R.; McLeod, D. R.; and 31 others: TMEM237
is mutated in individuals with a Joubert syndrome related disorder
and expands the role of the TMEM family at the ciliary transition
zone. Am. J. Hum. Genet. 89: 713-730, 2011.
4. Janecke, A. R.; Muller, T.; Gassner, I.; Kreczy, A.; Schmid, E.;
Kronenberg, F.; Utermann, B.; Utermann, G.: Joubert-like syndrome
unlinked to known candidate loci. J. Pediat. 144: 264-269, 2004.
5. Zuniga, F. I.; Craft, C. M.: Deciphering the structure and function
of Als2cr4 in the mouse retina. Invest. Ophthal. Vis. Sci. 51: 4407-4415,
2010.
*FIELD* CN
Ada Hamosh - updated: 2/11/2013
Cassandra L. Kniffin - updated: 1/11/2012
*FIELD* CD
Patricia A. Hartz: 1/10/2012
*FIELD* ED
carol: 09/06/2013
alopez: 2/11/2013
mgross: 1/19/2012
joanna: 1/18/2012
carol: 1/11/2012
ckniffin: 1/11/2012
mgross: 1/10/2012
MIM
614424
*RECORD*
*FIELD* NO
614424
*FIELD* TI
#614424 JOUBERT SYNDROME 14; JBTS14
*FIELD* TX
A number sign (#) is used with this entry because Joubert syndrome-14
read more(JBTS14) is caused by homozygous or compound heterozygous mutation in
the TMEM237 gene (614423) on chromosome 2q33.
DESCRIPTION
Joubert syndrome-14 is an autosomal recessive developmental disorder
characterized by severe mental retardation, hypoplasia of the cerebellar
vermis and molar tooth sign (MTS) on brain imaging, hypotonia, abnormal
breathing pattern in infancy, and dysmorphic facial features. Additional
findings can include renal cysts, abnormal eye movements, and postaxial
polydactyly (summary by Boycott et al., 2007 and Huang et al., 2011).
For a phenotypic description and a discussion of genetic heterogeneity
of Joubert syndrome, see 213300.
CLINICAL FEATURES
Boycott et al. (2007) reported 10 patients with Joubert syndrome in a
Canadian Hutterite population. Clinical features included severe to
profound developmental delay, hypotonia, ataxia, abnormal breathing
pattern, nystagmus, strabismus, and the molar tooth sign. The
characteristic facial features included a tall forehead, malar
flattening, hypertelorism, deep-set eyes, downslanting palpebral
fissures, ptosis, epicanthal folds, arched eyebrows, high nasal bridge,
short philtrum with tented upper lip, open mouth, and posteriorly
rotated low-set ears. Other variable features included retinal
colobomas, postaxial polydactyly, cystic kidneys, occipital
encephalocele, and posterior fossa abnormalities. There was increased
mortality. Seven of the patients had previously been diagnosed as having
Meckel syndrome (see, e.g., 249000). Boycott et al. (2007) also reviewed
a report of 3 Hutterite patients reported as having Meckel syndrome
(Schurig et al., 1980) and concluded that all had a variant of Joubert
syndrome. Mutations and deletions in the NPHP1 gene, as well as
evaluation of known loci for Meckel and Joubert syndrome, were all
excluded, suggesting further genetic heterogeneity.
Janecke et al. (2004) reported a consanguineous Austrian family in which
3 members had Joubert syndrome. The first affected infant showed an
irregular breathing pattern soon after birth. She had aplasia of the
cerebellar vermis, right-sided renal cyst, and poor psychomotor
development with hypotonia. She died of pneumonia at age 4 years. A
younger sib was noted to have meningocele, absence of the cerebellar
vermis, and cystic kidneys on prenatal ultrasound, and the pregnancy was
terminated. The third infant, born to another branch of this kindred,
had abnormal breathing in the first weeks of life, irregular, jerky eye
movements, aplasia of the cerebellar vermis, hypoplasia of the upper
brainstem, and multiple renal cysts. She had poor psychomotor
development and lack of speech. All 3 patients also had the morning
glory sign on funduscopic examination, consisting of an enlarged,
excavated disc with a central gliotic tuft and peripapillary pigment
changes. CT showed funnel-shaped optic discs. None had any evidence of
hepatic involvement. Linkage studies were inconclusive.
INHERITANCE
The transmission pattern in the families with Joubert syndrome-14
reported by Huang et al. (2011) was consistent with autosomal recessive
inheritance.
MAPPING
By genomewide homozygosity mapping in 4 Canadian Hutterite patients with
JBTS, Huang et al. (2011) found linkage to a 7.5-Mb region on chromosome
2q33. Mapping studies in a consanguineous Austrian family with the
disorder (Janecke et al., 2004) showed linkage to an overlapping region
on 2q33.
MOLECULAR GENETICS
By homozygosity mapping followed by candidate gene analysis in 10
related Canadian Hutterite families with Joubert syndrome-14 (Boycott et
al., 2007), Huang et al. (2011) identified a homozygous truncating
mutation in the TMEM237 gene (R18X; 614423.0001). Homozygous or compound
heterozygous mutations were also found in 3 additional families with the
disorder (614423.0002-614423.0005), including the family reported by
Janecke et al. (2004). All the mutations were predicted to result in a
null allele. Protein extracts from patient cells showed perturbation of
the noncanonical WNT (see 164820) pathway, with constitutive
phosphorylation and hyperactivation of DVL1 (601365) and an increase in
CTNNB1 (116806) levels.
POPULATION GENETICS
In a carrier screening of autosomal recessive mutations involving 1,644
Schmiedeleut (S-leut) Hutterites in the United States, Chong et al.
(2012) identified the Joubert syndrome mutation R18X (dbSNP rs199469707;
614423.0001) in heterozygous state in 122 individuals among 1,520
screened and in homozygous state in none, for a carrier frequency of
0.080 (1 in 12.5). This mutation is private to the Hutterite population.
*FIELD* RF
1. Boycott, K. M.; Parboosingh, J. S.; Scott, J. N.; McLeod, D. R.;
Greenberg, C. R.; Fujiwara, T. M.; Mah, J. K.; Midgley, J.; Wade,
A.; Bernier, F. P.; Chodirker, B. N.; Bunge, M.; Innes, A. M.: Meckel
syndrome in the Hutterite population is actually a Joubert-related
cerebello-oculo-renal syndrome. Am. J. Med. Genet. 143A: 1715-1725,
2007.
2. Chong, J. X.; Ouwenga, R.; Anderson, R. L.; Waggoner, D. J.; Ober,
C.: A population-based study of autosomal-recessive disease-causing
mutations in a founder population. Am. J. Hum. Genet. 91: 608-620,
2012.
3. Huang, L.; Szymanska, K.; Jensen, V. L.; Janecke, A. R.; Innes,
A. M.; Davis, E. E.; Frosk, P.; Li, C.; Willer, J. R.; Chodirker,
B. N.; Greenberg, C. R.; McLeod, D. R.; and 31 others: TMEM237 is
mutated in individuals with a Joubert syndrome related disorder and
expands the role of the TMEM family at the ciliary transition zone. Am.
J. Hum. Genet. 89: 713-730, 2011.
4. Janecke, A. R.; Muller, T.; Gassner, I.; Kreczy, A.; Schmid, E.;
Kronenberg, F.; Utermann, B.; Utermann, G.: Joubert-like syndrome
unlinked to known candidate loci. J. Pediat. 144: 264-269, 2004.
5. Schurig, V.; Bowen, P.; Harley, F.; Schiff, D.: The Meckel syndrome
in the Hutterites. Am. J. Med. Genet. 5: 373-382, 1980.
*FIELD* CS
INHERITANCE:
Autosomal recessive
GROWTH:
[Other];
Poor growth
HEAD AND NECK:
[Head];
Tall forehead;
[Face];
Short philtrum;
Malar flattening;
[Ears];
Posteriorly rotated ears;
Low-set ears;
[Eyes];
Hypertelorism;
Deep-set eyes;
Downslanting palpebral fissures;
Ptosis;
Epicanthal folds;
Microphthalmia;
Nystagmus;
Strabismus;
Coloboma;
Arched eyebrows;
Morning glory disc anomaly (1 family);
[Nose];
High nasal bridge;
[Mouth];
Tented upper lip;
Open mouth
CARDIOVASCULAR:
[Vascular];
Hypertension (variable)
RESPIRATORY:
Abnormal breathing pattern
GENITOURINARY:
[Kidneys];
Renal cysts
SKELETAL:
[Hands];
Postaxial polydactyly
MUSCLE, SOFT TISSUE:
Hypotonia
NEUROLOGIC:
[Central nervous system];
Delayed psychomotor development, severe to profound;
Mental retardation, severe;
Hypotonia;
Ataxia;
'Molar tooth sign' on MRI;
Posterior fossa abnormalities;
Small midbrain;
Hydrocephalus;
Encephalocele;
Cerebellar vermis aplasia or hypoplasia;
Dandy-Walker malformation;
[Behavioral/psychiatric manifestations];
Irritability
MISCELLANEOUS:
Death often occurs in the first decade
MOLECULAR BASIS:
Caused by mutation in the transmembrane protein 237 (TMEM237, 614423.0001)
*FIELD* CD
Cassandra L. Kniffin: 1/11/2012
*FIELD* ED
joanna: 02/28/2012
ckniffin: 1/11/2012
*FIELD* CN
Ada Hamosh - updated: 2/7/2013
*FIELD* CD
Cassandra L. Kniffin: 1/11/2012
*FIELD* ED
alopez: 02/11/2013
terry: 2/7/2013
carol: 1/11/2012
ckniffin: 1/11/2012
*RECORD*
*FIELD* NO
614424
*FIELD* TI
#614424 JOUBERT SYNDROME 14; JBTS14
*FIELD* TX
A number sign (#) is used with this entry because Joubert syndrome-14
read more(JBTS14) is caused by homozygous or compound heterozygous mutation in
the TMEM237 gene (614423) on chromosome 2q33.
DESCRIPTION
Joubert syndrome-14 is an autosomal recessive developmental disorder
characterized by severe mental retardation, hypoplasia of the cerebellar
vermis and molar tooth sign (MTS) on brain imaging, hypotonia, abnormal
breathing pattern in infancy, and dysmorphic facial features. Additional
findings can include renal cysts, abnormal eye movements, and postaxial
polydactyly (summary by Boycott et al., 2007 and Huang et al., 2011).
For a phenotypic description and a discussion of genetic heterogeneity
of Joubert syndrome, see 213300.
CLINICAL FEATURES
Boycott et al. (2007) reported 10 patients with Joubert syndrome in a
Canadian Hutterite population. Clinical features included severe to
profound developmental delay, hypotonia, ataxia, abnormal breathing
pattern, nystagmus, strabismus, and the molar tooth sign. The
characteristic facial features included a tall forehead, malar
flattening, hypertelorism, deep-set eyes, downslanting palpebral
fissures, ptosis, epicanthal folds, arched eyebrows, high nasal bridge,
short philtrum with tented upper lip, open mouth, and posteriorly
rotated low-set ears. Other variable features included retinal
colobomas, postaxial polydactyly, cystic kidneys, occipital
encephalocele, and posterior fossa abnormalities. There was increased
mortality. Seven of the patients had previously been diagnosed as having
Meckel syndrome (see, e.g., 249000). Boycott et al. (2007) also reviewed
a report of 3 Hutterite patients reported as having Meckel syndrome
(Schurig et al., 1980) and concluded that all had a variant of Joubert
syndrome. Mutations and deletions in the NPHP1 gene, as well as
evaluation of known loci for Meckel and Joubert syndrome, were all
excluded, suggesting further genetic heterogeneity.
Janecke et al. (2004) reported a consanguineous Austrian family in which
3 members had Joubert syndrome. The first affected infant showed an
irregular breathing pattern soon after birth. She had aplasia of the
cerebellar vermis, right-sided renal cyst, and poor psychomotor
development with hypotonia. She died of pneumonia at age 4 years. A
younger sib was noted to have meningocele, absence of the cerebellar
vermis, and cystic kidneys on prenatal ultrasound, and the pregnancy was
terminated. The third infant, born to another branch of this kindred,
had abnormal breathing in the first weeks of life, irregular, jerky eye
movements, aplasia of the cerebellar vermis, hypoplasia of the upper
brainstem, and multiple renal cysts. She had poor psychomotor
development and lack of speech. All 3 patients also had the morning
glory sign on funduscopic examination, consisting of an enlarged,
excavated disc with a central gliotic tuft and peripapillary pigment
changes. CT showed funnel-shaped optic discs. None had any evidence of
hepatic involvement. Linkage studies were inconclusive.
INHERITANCE
The transmission pattern in the families with Joubert syndrome-14
reported by Huang et al. (2011) was consistent with autosomal recessive
inheritance.
MAPPING
By genomewide homozygosity mapping in 4 Canadian Hutterite patients with
JBTS, Huang et al. (2011) found linkage to a 7.5-Mb region on chromosome
2q33. Mapping studies in a consanguineous Austrian family with the
disorder (Janecke et al., 2004) showed linkage to an overlapping region
on 2q33.
MOLECULAR GENETICS
By homozygosity mapping followed by candidate gene analysis in 10
related Canadian Hutterite families with Joubert syndrome-14 (Boycott et
al., 2007), Huang et al. (2011) identified a homozygous truncating
mutation in the TMEM237 gene (R18X; 614423.0001). Homozygous or compound
heterozygous mutations were also found in 3 additional families with the
disorder (614423.0002-614423.0005), including the family reported by
Janecke et al. (2004). All the mutations were predicted to result in a
null allele. Protein extracts from patient cells showed perturbation of
the noncanonical WNT (see 164820) pathway, with constitutive
phosphorylation and hyperactivation of DVL1 (601365) and an increase in
CTNNB1 (116806) levels.
POPULATION GENETICS
In a carrier screening of autosomal recessive mutations involving 1,644
Schmiedeleut (S-leut) Hutterites in the United States, Chong et al.
(2012) identified the Joubert syndrome mutation R18X (dbSNP rs199469707;
614423.0001) in heterozygous state in 122 individuals among 1,520
screened and in homozygous state in none, for a carrier frequency of
0.080 (1 in 12.5). This mutation is private to the Hutterite population.
*FIELD* RF
1. Boycott, K. M.; Parboosingh, J. S.; Scott, J. N.; McLeod, D. R.;
Greenberg, C. R.; Fujiwara, T. M.; Mah, J. K.; Midgley, J.; Wade,
A.; Bernier, F. P.; Chodirker, B. N.; Bunge, M.; Innes, A. M.: Meckel
syndrome in the Hutterite population is actually a Joubert-related
cerebello-oculo-renal syndrome. Am. J. Med. Genet. 143A: 1715-1725,
2007.
2. Chong, J. X.; Ouwenga, R.; Anderson, R. L.; Waggoner, D. J.; Ober,
C.: A population-based study of autosomal-recessive disease-causing
mutations in a founder population. Am. J. Hum. Genet. 91: 608-620,
2012.
3. Huang, L.; Szymanska, K.; Jensen, V. L.; Janecke, A. R.; Innes,
A. M.; Davis, E. E.; Frosk, P.; Li, C.; Willer, J. R.; Chodirker,
B. N.; Greenberg, C. R.; McLeod, D. R.; and 31 others: TMEM237 is
mutated in individuals with a Joubert syndrome related disorder and
expands the role of the TMEM family at the ciliary transition zone. Am.
J. Hum. Genet. 89: 713-730, 2011.
4. Janecke, A. R.; Muller, T.; Gassner, I.; Kreczy, A.; Schmid, E.;
Kronenberg, F.; Utermann, B.; Utermann, G.: Joubert-like syndrome
unlinked to known candidate loci. J. Pediat. 144: 264-269, 2004.
5. Schurig, V.; Bowen, P.; Harley, F.; Schiff, D.: The Meckel syndrome
in the Hutterites. Am. J. Med. Genet. 5: 373-382, 1980.
*FIELD* CS
INHERITANCE:
Autosomal recessive
GROWTH:
[Other];
Poor growth
HEAD AND NECK:
[Head];
Tall forehead;
[Face];
Short philtrum;
Malar flattening;
[Ears];
Posteriorly rotated ears;
Low-set ears;
[Eyes];
Hypertelorism;
Deep-set eyes;
Downslanting palpebral fissures;
Ptosis;
Epicanthal folds;
Microphthalmia;
Nystagmus;
Strabismus;
Coloboma;
Arched eyebrows;
Morning glory disc anomaly (1 family);
[Nose];
High nasal bridge;
[Mouth];
Tented upper lip;
Open mouth
CARDIOVASCULAR:
[Vascular];
Hypertension (variable)
RESPIRATORY:
Abnormal breathing pattern
GENITOURINARY:
[Kidneys];
Renal cysts
SKELETAL:
[Hands];
Postaxial polydactyly
MUSCLE, SOFT TISSUE:
Hypotonia
NEUROLOGIC:
[Central nervous system];
Delayed psychomotor development, severe to profound;
Mental retardation, severe;
Hypotonia;
Ataxia;
'Molar tooth sign' on MRI;
Posterior fossa abnormalities;
Small midbrain;
Hydrocephalus;
Encephalocele;
Cerebellar vermis aplasia or hypoplasia;
Dandy-Walker malformation;
[Behavioral/psychiatric manifestations];
Irritability
MISCELLANEOUS:
Death often occurs in the first decade
MOLECULAR BASIS:
Caused by mutation in the transmembrane protein 237 (TMEM237, 614423.0001)
*FIELD* CD
Cassandra L. Kniffin: 1/11/2012
*FIELD* ED
joanna: 02/28/2012
ckniffin: 1/11/2012
*FIELD* CN
Ada Hamosh - updated: 2/7/2013
*FIELD* CD
Cassandra L. Kniffin: 1/11/2012
*FIELD* ED
alopez: 02/11/2013
terry: 2/7/2013
carol: 1/11/2012
ckniffin: 1/11/2012