Full text data of TTC37
TTC37
(KIAA0372)
[Confidence: low (only semi-automatic identification from reviews)]
Tetratricopeptide repeat protein 37; TPR repeat protein 37 (SKI3 homolog; Ski3; Tricho-hepatic-enteric syndrome protein; Thespin)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Tetratricopeptide repeat protein 37; TPR repeat protein 37 (SKI3 homolog; Ski3; Tricho-hepatic-enteric syndrome protein; Thespin)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
Q6PGP7
ID TTC37_HUMAN Reviewed; 1564 AA.
AC Q6PGP7; O15077; Q6PJI3;
DT 03-OCT-2006, integrated into UniProtKB/Swiss-Prot.
read moreDT 05-JUL-2004, sequence version 1.
DT 22-JAN-2014, entry version 93.
DE RecName: Full=Tetratricopeptide repeat protein 37;
DE Short=TPR repeat protein 37;
DE AltName: Full=SKI3 homolog;
DE Short=Ski3;
DE AltName: Full=Tricho-hepatic-enteric syndrome protein;
DE Short=Thespin;
GN Name=TTC37; Synonyms=KIAA0372;
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 [LARGE SCALE MRNA].
RC TISSUE=Brain;
RX PubMed=9205841; DOI=10.1093/dnares/4.2.141;
RA Nagase T., Ishikawa K., Nakajima D., Ohira M., Seki N., Miyajima N.,
RA Tanaka A., Kotani H., Nomura N., Ohara O.;
RT "Prediction of the coding sequences of unidentified human genes. VII.
RT The complete sequences of 100 new cDNA clones from brain which can
RT code for large proteins in vitro.";
RL DNA Res. 4:141-150(1997).
RN [2]
RP SEQUENCE REVISION.
RA Ohara O., Nagase T., Kikuno R., Nomura N.;
RL Submitted (JAN-2004) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Lung carcinoma, and Melanoma;
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 [4]
RP SUBCELLULAR LOCATION, INTERACTION WITH PAF1, AND IDENTIFICATION IN THE
RP SKI COMPLEX.
RX PubMed=16024656; DOI=10.1101/gad.1292105;
RA Zhu B., Mandal S.S., Pham A.D., Zheng Y., Erdjument-Bromage H.,
RA Batra S.K., Tempst P., Reinberg D.;
RT "The human PAF complex coordinates transcription with events
RT downstream of RNA synthesis.";
RL Genes Dev. 19:1668-1673(2005).
RN [5]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [6]
RP TISSUE SPECIFICITY, VARIANTS 860-ASN--GLU-878 DEL; ASP-1077; ALA-1270
RP AND ARG-1485, AND ASSOCIATION WITH THES1.
RX PubMed=21120949; DOI=10.1002/humu.21420;
RA Fabre A., Martinez-Vinson C., Roquelaure B., Missirian C., Andre N.,
RA Breton A., Lachaux A., Odul E., Colomb V., Lemale J., Cezard J.P.,
RA Goulet O., Sarles J., Levy N., Badens C.;
RT "Novel mutations in TTC37 associated with Tricho-Hepato-Enteric
RT syndrome.";
RL Hum. Mutat. 32:277-281(2011).
RN [7]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT SER-2, MASS SPECTROMETRY, AND
RP CLEAVAGE OF INITIATOR METHIONINE.
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [8]
RP VARIANTS THES1 ARG-251; ASN-1283 AND SER-1505.
RX PubMed=20176027; DOI=10.1053/j.gastro.2010.02.010;
RA Hartley J.L., Zachos N.C., Dawood B., Donowitz M., Forman J.,
RA Pollitt R.J., Morgan N.V., Tee L., Gissen P., Kahr W.H., Knisely A.S.,
RA Watson S., Chitayat D., Booth I.W., Protheroe S., Murphy S.,
RA de Vries E., Kelly D.A., Maher E.R.;
RT "Mutations in TTC37 cause trichohepatoenteric syndrome (phenotypic
RT diarrhea of infancy).";
RL Gastroenterology 138:2388-2398(2010).
CC -!- FUNCTION: Component of the SKI complex which is thought to be
CC involved in exosome-mediated RNA decay and associates with
CC transcriptionally active genes in a manner dependent on PAF1
CC complex (PAF1C).
CC -!- SUBUNIT: Component of the SKI complex which consists of WDR61,
CC SKIV2L and TTC37. Interacts with PAF1.
CC -!- INTERACTION:
CC Q8N7H5:PAF1; NbExp=2; IntAct=EBI-6083436, EBI-2607770;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus.
CC -!- TISSUE SPECIFICITY: Widely expressed with the highest levels
CC observed in vascular tissues, lymph node, pituitary, lung and
CC intestine. Not expressed in the liver.
CC -!- DISEASE: Trichohepatoenteric syndrome 1 (THES1) [MIM:222470]: A
CC syndrome characterized by intrauterine growth retardation, severe
CC diarrhea in infancy requiring total parenteral nutrition, facial
CC dysmorphism, immunodeficiency, and hair abnormalities, mostly
CC trichorrhexis nodosa. Hepatic involvement contributes to the poor
CC prognosis of affected patients. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Contains 20 TPR repeats.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAA20827.2; Type=Erroneous initiation; Note=Translation N-terminally shortened;
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; AB002370; BAA20827.2; ALT_INIT; mRNA.
DR EMBL; BC015163; AAH15163.1; -; mRNA.
DR EMBL; BC056893; AAH56893.1; -; mRNA.
DR RefSeq; NP_055454.1; NM_014639.3.
DR UniGene; Hs.482868; -.
DR ProteinModelPortal; Q6PGP7; -.
DR SMR; Q6PGP7; 395-701, 849-902.
DR IntAct; Q6PGP7; 5.
DR MINT; MINT-1194694; -.
DR STRING; 9606.ENSP00000351596; -.
DR PhosphoSite; Q6PGP7; -.
DR DMDM; 74758339; -.
DR PaxDb; Q6PGP7; -.
DR PeptideAtlas; Q6PGP7; -.
DR PRIDE; Q6PGP7; -.
DR Ensembl; ENST00000358746; ENSP00000351596; ENSG00000198677.
DR GeneID; 9652; -.
DR KEGG; hsa:9652; -.
DR UCSC; uc003klb.3; human.
DR CTD; 9652; -.
DR GeneCards; GC05M094826; -.
DR HGNC; HGNC:23639; TTC37.
DR HPA; HPA037905; -.
DR MIM; 222470; phenotype.
DR MIM; 614589; gene.
DR neXtProt; NX_Q6PGP7; -.
DR Orphanet; 84064; Syndromic diarrhea.
DR PharmGKB; PA162407226; -.
DR eggNOG; COG0457; -.
DR HOGENOM; HOG000154707; -.
DR HOVERGEN; HBG090717; -.
DR InParanoid; Q6PGP7; -.
DR KO; K12600; -.
DR OMA; NTQPKRM; -.
DR OrthoDB; EOG7JHM4S; -.
DR PhylomeDB; Q6PGP7; -.
DR ChiTaRS; TTC37; human.
DR GenomeRNAi; 9652; -.
DR NextBio; 36233; -.
DR PRO; PR:Q6PGP7; -.
DR ArrayExpress; Q6PGP7; -.
DR Bgee; Q6PGP7; -.
DR CleanEx; HS_TTC37; -.
DR Genevestigator; Q6PGP7; -.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0055087; C:Ski complex; IDA:UniProtKB.
DR GO; GO:0035327; C:transcriptionally active chromatin; IDA:UniProtKB.
DR Gene3D; 1.25.40.10; -; 8.
DR InterPro; IPR006597; Sel1-like.
DR InterPro; IPR013026; TPR-contain_dom.
DR InterPro; IPR011990; TPR-like_helical.
DR InterPro; IPR001440; TPR_1.
DR InterPro; IPR019734; TPR_repeat.
DR Pfam; PF00515; TPR_1; 2.
DR Pfam; PF13181; TPR_8; 1.
DR SMART; SM00671; SEL1; 2.
DR SMART; SM00028; TPR; 14.
DR PROSITE; PS50005; TPR; 12.
DR PROSITE; PS50293; TPR_REGION; 5.
PE 1: Evidence at protein level;
KW Acetylation; Complete proteome; Cytoplasm; Nucleus; Polymorphism;
KW Reference proteome; Repeat; TPR repeat.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 1564 Tetratricopeptide repeat protein 37.
FT /FTId=PRO_0000251722.
FT REPEAT 6 39 TPR 1.
FT REPEAT 40 73 TPR 2.
FT REPEAT 272 305 TPR 3.
FT REPEAT 307 339 TPR 4.
FT REPEAT 386 419 TPR 5.
FT REPEAT 420 453 TPR 6.
FT REPEAT 455 492 TPR 7.
FT REPEAT 493 527 TPR 8.
FT REPEAT 564 597 TPR 9.
FT REPEAT 598 631 TPR 10.
FT REPEAT 633 665 TPR 11.
FT REPEAT 679 713 TPR 12.
FT REPEAT 790 824 TPR 13.
FT REPEAT 826 860 TPR 14.
FT REPEAT 861 894 TPR 15.
FT REPEAT 980 1013 TPR 16.
FT REPEAT 1020 1054 TPR 17.
FT REPEAT 1056 1084 TPR 18.
FT REPEAT 1326 1359 TPR 19.
FT REPEAT 1400 1433 TPR 20.
FT MOD_RES 2 2 N-acetylserine.
FT VARIANT 251 251 G -> R (in THES1).
FT /FTId=VAR_067957.
FT VARIANT 437 437 L -> V (in dbSNP:rs17084873).
FT /FTId=VAR_027705.
FT VARIANT 860 878 Missing (found in a THES1 patient).
FT /FTId=VAR_065297.
FT VARIANT 1077 1077 A -> D (found in a THES1 patient).
FT /FTId=VAR_065298.
FT VARIANT 1270 1270 P -> A (found in a THES1 patient).
FT /FTId=VAR_065299.
FT VARIANT 1283 1283 D -> N (in THES1).
FT /FTId=VAR_067958.
FT VARIANT 1296 1296 R -> S (in dbSNP:rs2303650).
FT /FTId=VAR_027706.
FT VARIANT 1485 1485 L -> R (found in a THES1 patient).
FT /FTId=VAR_065300.
FT VARIANT 1505 1505 L -> S (in THES1).
FT /FTId=VAR_067959.
SQ SEQUENCE 1564 AA; 175486 MW; 12D6B45B4A6F367A CRC64;
MSSKEVKTAL KSARDAIRNK EYKEALKHCK TVLKQEKNNY NAWVFIGVAA AELEQPDQAQ
SAYKKAAELE PDQLLAWQGL ANLYEKYNHI NAKDDLPGVY QKLLDLYESV DKQKWCDVCK
KLVDLYYQEK KHLEVARTWH KLIKTRQEQG AENEELHQLW RKLTQFLAES TEDQNNETQQ
LLFTAFENAL GLSDKIPSED HQVLYRHFIQ SLSKFPHESA RLKKACEGMI NIYPTVQYPL
EVLCLHLIES GNLTDEGQQY CCRLVEMDSK SGPGLIGLGI KALQDKKYED AVRNLTEGLK
ESPVCTSGWY HLAEAQVKMH RPKEAVLSCS QALKIVDNLG ASGNSLYQRN LCLHLKAEAL
IKLSDYDSSE EAIRTLDQIS DADNIPGLLV LKSLAYRNKG SFDEAAKIME DLLSSYPDLA
EVHALEALIH FTKKDYLQAE KCFQRALEKD TEVAEYHYQL GLTYWFMGEE TRKDKTKALT
HFLKAARLDT YMGKVFCYLG HYYRDVVGDK NRARGCYRKA FELDDTDAES GAAAVDLSVE
LEDMEMALAI LTTVTQKASA GTAKWAWLRR GLYYLKAGQH SQAVADLQAA LRADPKDFNC
WESLGEAYLS RGGYTTALKS FTKASELNPE SIYSVFKVAA IQQILGKYKE AVAQYQMIIK
KKEDYVPALK GLGECHLMMA KAALVDYLDG KAVDYIEKAL EYFTCALQHR ADVSCLWKLA
GDACTCLYAV APSKVNVHVL GVLLGQKEGK QVLKKNELLH LGGRCYGRAL KLMSTSNTWC
DLGINYYRQA QHLAETGSNM NDLKELLEKS LHCLKKAVRL DSNNHLYWNA LGVVACYSGI
GNYALAQHCF IKSIQSEQIN AVAWTNLGVL YLTNENIEQA HEAFKMAQSL DPSYLMCWIG
QALIAEAVGS YDTMDLFRHT TELNMHTEGA LGYAYWVCTT LQDKSNRETE LYQYNILQMN
AIPAAQVILN KYVERIQNYA PAFTMLGYLN EHLQLKKEAA NAYQRAILLL QTAEDQDTYN
VAIRNYGRLL CSTGEYDKAI QAFKSTPLEV LEDIIGFALA LFMKGLYKES SKAYERALSI
VESEQDKAHI LTALAITEYK QGKTDVAKTL LFKCSILKEP TTESLQALCA LGLAMQDATL
SKAALNELLK HIKHKDSNYQ RCLLTSAIYA LQGRSVAVQK QISKAVHSNP GDPALWSLLS
RVVAQYAQRN AKGGVVAGNV AHILDSNHGK KALLYTAVNQ LAMGSSSAED EKNTALKTIQ
KAALLSPGDP AIWAGLMAAC HADDKLALVN NTQPKRIDLY LALLSAVSAS IKDEKFFENY
NQSLEKWSLS QAVTGLIDTG RISEAETLCT KNLKSNPDQP AVILLLRQVQ CKPLLESQKP
LPDAVLEELQ KTVMSNSTSV PAWQWLAHVY QSQGMMRAAE MCYRKSLQLA SQRGSWSGKL
SSLLRLALLA LKVCMANISN DHWPSLVQEA TTEALKLCFC PLAVLLQALL QFKRKMGARE
TRRLLERVVY QPGYPKSIAS TARWYLLRHL YAKDDYELID VLVNNAKTHG DTRALELNQR
LSSQ
//
ID TTC37_HUMAN Reviewed; 1564 AA.
AC Q6PGP7; O15077; Q6PJI3;
DT 03-OCT-2006, integrated into UniProtKB/Swiss-Prot.
read moreDT 05-JUL-2004, sequence version 1.
DT 22-JAN-2014, entry version 93.
DE RecName: Full=Tetratricopeptide repeat protein 37;
DE Short=TPR repeat protein 37;
DE AltName: Full=SKI3 homolog;
DE Short=Ski3;
DE AltName: Full=Tricho-hepatic-enteric syndrome protein;
DE Short=Thespin;
GN Name=TTC37; Synonyms=KIAA0372;
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 [LARGE SCALE MRNA].
RC TISSUE=Brain;
RX PubMed=9205841; DOI=10.1093/dnares/4.2.141;
RA Nagase T., Ishikawa K., Nakajima D., Ohira M., Seki N., Miyajima N.,
RA Tanaka A., Kotani H., Nomura N., Ohara O.;
RT "Prediction of the coding sequences of unidentified human genes. VII.
RT The complete sequences of 100 new cDNA clones from brain which can
RT code for large proteins in vitro.";
RL DNA Res. 4:141-150(1997).
RN [2]
RP SEQUENCE REVISION.
RA Ohara O., Nagase T., Kikuno R., Nomura N.;
RL Submitted (JAN-2004) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Lung carcinoma, and Melanoma;
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 [4]
RP SUBCELLULAR LOCATION, INTERACTION WITH PAF1, AND IDENTIFICATION IN THE
RP SKI COMPLEX.
RX PubMed=16024656; DOI=10.1101/gad.1292105;
RA Zhu B., Mandal S.S., Pham A.D., Zheng Y., Erdjument-Bromage H.,
RA Batra S.K., Tempst P., Reinberg D.;
RT "The human PAF complex coordinates transcription with events
RT downstream of RNA synthesis.";
RL Genes Dev. 19:1668-1673(2005).
RN [5]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [6]
RP TISSUE SPECIFICITY, VARIANTS 860-ASN--GLU-878 DEL; ASP-1077; ALA-1270
RP AND ARG-1485, AND ASSOCIATION WITH THES1.
RX PubMed=21120949; DOI=10.1002/humu.21420;
RA Fabre A., Martinez-Vinson C., Roquelaure B., Missirian C., Andre N.,
RA Breton A., Lachaux A., Odul E., Colomb V., Lemale J., Cezard J.P.,
RA Goulet O., Sarles J., Levy N., Badens C.;
RT "Novel mutations in TTC37 associated with Tricho-Hepato-Enteric
RT syndrome.";
RL Hum. Mutat. 32:277-281(2011).
RN [7]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT SER-2, MASS SPECTROMETRY, AND
RP CLEAVAGE OF INITIATOR METHIONINE.
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [8]
RP VARIANTS THES1 ARG-251; ASN-1283 AND SER-1505.
RX PubMed=20176027; DOI=10.1053/j.gastro.2010.02.010;
RA Hartley J.L., Zachos N.C., Dawood B., Donowitz M., Forman J.,
RA Pollitt R.J., Morgan N.V., Tee L., Gissen P., Kahr W.H., Knisely A.S.,
RA Watson S., Chitayat D., Booth I.W., Protheroe S., Murphy S.,
RA de Vries E., Kelly D.A., Maher E.R.;
RT "Mutations in TTC37 cause trichohepatoenteric syndrome (phenotypic
RT diarrhea of infancy).";
RL Gastroenterology 138:2388-2398(2010).
CC -!- FUNCTION: Component of the SKI complex which is thought to be
CC involved in exosome-mediated RNA decay and associates with
CC transcriptionally active genes in a manner dependent on PAF1
CC complex (PAF1C).
CC -!- SUBUNIT: Component of the SKI complex which consists of WDR61,
CC SKIV2L and TTC37. Interacts with PAF1.
CC -!- INTERACTION:
CC Q8N7H5:PAF1; NbExp=2; IntAct=EBI-6083436, EBI-2607770;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus.
CC -!- TISSUE SPECIFICITY: Widely expressed with the highest levels
CC observed in vascular tissues, lymph node, pituitary, lung and
CC intestine. Not expressed in the liver.
CC -!- DISEASE: Trichohepatoenteric syndrome 1 (THES1) [MIM:222470]: A
CC syndrome characterized by intrauterine growth retardation, severe
CC diarrhea in infancy requiring total parenteral nutrition, facial
CC dysmorphism, immunodeficiency, and hair abnormalities, mostly
CC trichorrhexis nodosa. Hepatic involvement contributes to the poor
CC prognosis of affected patients. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Contains 20 TPR repeats.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAA20827.2; Type=Erroneous initiation; Note=Translation N-terminally shortened;
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; AB002370; BAA20827.2; ALT_INIT; mRNA.
DR EMBL; BC015163; AAH15163.1; -; mRNA.
DR EMBL; BC056893; AAH56893.1; -; mRNA.
DR RefSeq; NP_055454.1; NM_014639.3.
DR UniGene; Hs.482868; -.
DR ProteinModelPortal; Q6PGP7; -.
DR SMR; Q6PGP7; 395-701, 849-902.
DR IntAct; Q6PGP7; 5.
DR MINT; MINT-1194694; -.
DR STRING; 9606.ENSP00000351596; -.
DR PhosphoSite; Q6PGP7; -.
DR DMDM; 74758339; -.
DR PaxDb; Q6PGP7; -.
DR PeptideAtlas; Q6PGP7; -.
DR PRIDE; Q6PGP7; -.
DR Ensembl; ENST00000358746; ENSP00000351596; ENSG00000198677.
DR GeneID; 9652; -.
DR KEGG; hsa:9652; -.
DR UCSC; uc003klb.3; human.
DR CTD; 9652; -.
DR GeneCards; GC05M094826; -.
DR HGNC; HGNC:23639; TTC37.
DR HPA; HPA037905; -.
DR MIM; 222470; phenotype.
DR MIM; 614589; gene.
DR neXtProt; NX_Q6PGP7; -.
DR Orphanet; 84064; Syndromic diarrhea.
DR PharmGKB; PA162407226; -.
DR eggNOG; COG0457; -.
DR HOGENOM; HOG000154707; -.
DR HOVERGEN; HBG090717; -.
DR InParanoid; Q6PGP7; -.
DR KO; K12600; -.
DR OMA; NTQPKRM; -.
DR OrthoDB; EOG7JHM4S; -.
DR PhylomeDB; Q6PGP7; -.
DR ChiTaRS; TTC37; human.
DR GenomeRNAi; 9652; -.
DR NextBio; 36233; -.
DR PRO; PR:Q6PGP7; -.
DR ArrayExpress; Q6PGP7; -.
DR Bgee; Q6PGP7; -.
DR CleanEx; HS_TTC37; -.
DR Genevestigator; Q6PGP7; -.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0055087; C:Ski complex; IDA:UniProtKB.
DR GO; GO:0035327; C:transcriptionally active chromatin; IDA:UniProtKB.
DR Gene3D; 1.25.40.10; -; 8.
DR InterPro; IPR006597; Sel1-like.
DR InterPro; IPR013026; TPR-contain_dom.
DR InterPro; IPR011990; TPR-like_helical.
DR InterPro; IPR001440; TPR_1.
DR InterPro; IPR019734; TPR_repeat.
DR Pfam; PF00515; TPR_1; 2.
DR Pfam; PF13181; TPR_8; 1.
DR SMART; SM00671; SEL1; 2.
DR SMART; SM00028; TPR; 14.
DR PROSITE; PS50005; TPR; 12.
DR PROSITE; PS50293; TPR_REGION; 5.
PE 1: Evidence at protein level;
KW Acetylation; Complete proteome; Cytoplasm; Nucleus; Polymorphism;
KW Reference proteome; Repeat; TPR repeat.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 1564 Tetratricopeptide repeat protein 37.
FT /FTId=PRO_0000251722.
FT REPEAT 6 39 TPR 1.
FT REPEAT 40 73 TPR 2.
FT REPEAT 272 305 TPR 3.
FT REPEAT 307 339 TPR 4.
FT REPEAT 386 419 TPR 5.
FT REPEAT 420 453 TPR 6.
FT REPEAT 455 492 TPR 7.
FT REPEAT 493 527 TPR 8.
FT REPEAT 564 597 TPR 9.
FT REPEAT 598 631 TPR 10.
FT REPEAT 633 665 TPR 11.
FT REPEAT 679 713 TPR 12.
FT REPEAT 790 824 TPR 13.
FT REPEAT 826 860 TPR 14.
FT REPEAT 861 894 TPR 15.
FT REPEAT 980 1013 TPR 16.
FT REPEAT 1020 1054 TPR 17.
FT REPEAT 1056 1084 TPR 18.
FT REPEAT 1326 1359 TPR 19.
FT REPEAT 1400 1433 TPR 20.
FT MOD_RES 2 2 N-acetylserine.
FT VARIANT 251 251 G -> R (in THES1).
FT /FTId=VAR_067957.
FT VARIANT 437 437 L -> V (in dbSNP:rs17084873).
FT /FTId=VAR_027705.
FT VARIANT 860 878 Missing (found in a THES1 patient).
FT /FTId=VAR_065297.
FT VARIANT 1077 1077 A -> D (found in a THES1 patient).
FT /FTId=VAR_065298.
FT VARIANT 1270 1270 P -> A (found in a THES1 patient).
FT /FTId=VAR_065299.
FT VARIANT 1283 1283 D -> N (in THES1).
FT /FTId=VAR_067958.
FT VARIANT 1296 1296 R -> S (in dbSNP:rs2303650).
FT /FTId=VAR_027706.
FT VARIANT 1485 1485 L -> R (found in a THES1 patient).
FT /FTId=VAR_065300.
FT VARIANT 1505 1505 L -> S (in THES1).
FT /FTId=VAR_067959.
SQ SEQUENCE 1564 AA; 175486 MW; 12D6B45B4A6F367A CRC64;
MSSKEVKTAL KSARDAIRNK EYKEALKHCK TVLKQEKNNY NAWVFIGVAA AELEQPDQAQ
SAYKKAAELE PDQLLAWQGL ANLYEKYNHI NAKDDLPGVY QKLLDLYESV DKQKWCDVCK
KLVDLYYQEK KHLEVARTWH KLIKTRQEQG AENEELHQLW RKLTQFLAES TEDQNNETQQ
LLFTAFENAL GLSDKIPSED HQVLYRHFIQ SLSKFPHESA RLKKACEGMI NIYPTVQYPL
EVLCLHLIES GNLTDEGQQY CCRLVEMDSK SGPGLIGLGI KALQDKKYED AVRNLTEGLK
ESPVCTSGWY HLAEAQVKMH RPKEAVLSCS QALKIVDNLG ASGNSLYQRN LCLHLKAEAL
IKLSDYDSSE EAIRTLDQIS DADNIPGLLV LKSLAYRNKG SFDEAAKIME DLLSSYPDLA
EVHALEALIH FTKKDYLQAE KCFQRALEKD TEVAEYHYQL GLTYWFMGEE TRKDKTKALT
HFLKAARLDT YMGKVFCYLG HYYRDVVGDK NRARGCYRKA FELDDTDAES GAAAVDLSVE
LEDMEMALAI LTTVTQKASA GTAKWAWLRR GLYYLKAGQH SQAVADLQAA LRADPKDFNC
WESLGEAYLS RGGYTTALKS FTKASELNPE SIYSVFKVAA IQQILGKYKE AVAQYQMIIK
KKEDYVPALK GLGECHLMMA KAALVDYLDG KAVDYIEKAL EYFTCALQHR ADVSCLWKLA
GDACTCLYAV APSKVNVHVL GVLLGQKEGK QVLKKNELLH LGGRCYGRAL KLMSTSNTWC
DLGINYYRQA QHLAETGSNM NDLKELLEKS LHCLKKAVRL DSNNHLYWNA LGVVACYSGI
GNYALAQHCF IKSIQSEQIN AVAWTNLGVL YLTNENIEQA HEAFKMAQSL DPSYLMCWIG
QALIAEAVGS YDTMDLFRHT TELNMHTEGA LGYAYWVCTT LQDKSNRETE LYQYNILQMN
AIPAAQVILN KYVERIQNYA PAFTMLGYLN EHLQLKKEAA NAYQRAILLL QTAEDQDTYN
VAIRNYGRLL CSTGEYDKAI QAFKSTPLEV LEDIIGFALA LFMKGLYKES SKAYERALSI
VESEQDKAHI LTALAITEYK QGKTDVAKTL LFKCSILKEP TTESLQALCA LGLAMQDATL
SKAALNELLK HIKHKDSNYQ RCLLTSAIYA LQGRSVAVQK QISKAVHSNP GDPALWSLLS
RVVAQYAQRN AKGGVVAGNV AHILDSNHGK KALLYTAVNQ LAMGSSSAED EKNTALKTIQ
KAALLSPGDP AIWAGLMAAC HADDKLALVN NTQPKRIDLY LALLSAVSAS IKDEKFFENY
NQSLEKWSLS QAVTGLIDTG RISEAETLCT KNLKSNPDQP AVILLLRQVQ CKPLLESQKP
LPDAVLEELQ KTVMSNSTSV PAWQWLAHVY QSQGMMRAAE MCYRKSLQLA SQRGSWSGKL
SSLLRLALLA LKVCMANISN DHWPSLVQEA TTEALKLCFC PLAVLLQALL QFKRKMGARE
TRRLLERVVY QPGYPKSIAS TARWYLLRHL YAKDDYELID VLVNNAKTHG DTRALELNQR
LSSQ
//
MIM
222470
*RECORD*
*FIELD* NO
222470
*FIELD* TI
#222470 TRICHOHEPATOENTERIC SYNDROME 1; THES1
;;THE SYNDROME;;
DIARRHEA, SYNDROMIC;;
read moreDIARRHEA, FATAL INFANTILE, WITH TRICHORRHEXIS NODOSA
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
trichohepatoenteric syndrome-1 (THES1) is caused by homozygous or
compound heterozygous mutation in the TTC37 gene (614589) on chromosome
5q15.
DESCRIPTION
Although the spectrum of phenotypic expression in trichohepatoenteric
syndrome (THES) is broad, the characteristic features include
intrauterine growth retardation, woolly hair, facial dysmorphism,
intractable diarrhea in infancy requiring total parenteral nutrition,
and immunodepression. Hepatic involvement contributes to the poor
prognosis of affected patients (summary by Fabre et al., 2007).
- Genetic Heterogeneity of Trichohepatoenteric Syndrome
Trichohepatoenteric syndrome-2 (THES2; 614602) is caused by mutation in
the SKIV2L gene (600478) on chromosome 6p21.3.
CLINICAL FEATURES
Stankler et al. (1982) reported a seemingly 'new,' presumably autosomal
recessive disorder in a sister and brother who died at 33 and 87 days of
age, respectively, with severe unexplained diarrhea. Both were of low
birth weight for dates and had large, low-set, simple ears, flat nasal
bridge, and large mouth. Both had woolly, easily removed black hair
showing an abnormality the authors dubbed 'trichorrhexis blastysis.' By
scanning microscopy, the hairs showed projections at multiple sites
arising from the convex surface of a kinked hair and suggesting buds
(Gr. blastosis = bud). The hair had a low content of cystine and an
abnormal content of several other amino acids. Both parents had normal
hair microscopically and chemically. In both sibs, the diarrhea began in
the third week of life and was preceded by excoriated buttocks. Both had
galactosuria without galactosemia. At autopsy both had hepatic fibrosis
and hemosiderosis and islet cell hyperplasia. Menkes disease (309400)
and argininosuccinic aciduria (207900), which have somewhat similar
findings in the hair, were excluded by chemical tests.
Girault et al. (1994) reported 8 children with severe secretory diarrhea
beginning in the first 6 months of life (less than 1 month in 6 cases).
All were small for gestational age and had facial dysmorphism and
woolly, easily removable hair with trichorrhexis nodosa. Two children
were from consanguineous marriages. Diarrhea was refractive to therapy,
including bowel rest. All patients had jejunal biopsies that showed
total or subtotal villous atrophy, defective antigen-specific skin
tests, and defective antibody responses despite normal serum
immunoglobulin levels. Two patients had hepatic cirrhosis, and 3
children had mental retardation. At the time of the report, 5 patients
had died between the ages of 2 and 5 years, 2 were fed enterally, and 1
continued to receive total parenteral nutrition. Barabino et al. (2004)
reported follow-up of the patient dependent on parenteral nutrition
reported by Girault et al. (1994). At age 6 years, she achieved
intestinal autonomy with discontinuation of the parenteral nutrition. At
age 14 years, she had mild psychomotor and pubertal delay. She had
chronic malabsorptive diarrhea, hypoalbuminemia, iron-deficiency anemia,
osteoporosis, and impaired intestinal permeability. Immunologic defect
was still present, but no other infections were recorded.
Verloes et al. (1997) used the term 'tricho-hepato-enteric syndrome' to
describe the disorder in a brother and sister who were noted prenatally
to have intrauterine growth retardation, hydramnios, and placental
hyperplasia. Both had intractable diarrhea with normal histologic and
enzymologic studies. Facial anomalies included hypertelorism, upturned
noses, small mouths, and low-set ears. Hair texture and pattern were
abnormal. Neurologically, they appeared grossly normal. The sister was
noted to have cholestatic jaundice and hepatomegaly at 2 months of age,
whereas the brother was noted to have hepatic dysfunction at birth with
a high alpha-fetoprotein level. He also had mild and delayed
hypermethioninemia. Both died at about 6 months of age. Pathologic
examination of both children showed a similar pattern of multivisceral
iron deposition compatible with a diagnosis of neonatal hemochromatosis,
although the clinical picture of an asymptomatic neonatal period was
unusual.
Goulet et al. (1998) studied the clinical and histopathologic features
of 47 infants with intractable diarrhea and villous atrophy of varying
degrees, dividing them into 2 groups, with or without lamina propria
mononuclear cell infiltration. Of the 18 patients in the latter group, 8
had phenotypic abnormalities including facial dysmorphism and abnormal
hair; 6 of the 8 patients had previously been reported by Girault et al.
(1994).
Landers and Schroeder (2003) reported a 3-year-old girl with severe
intractable diarrhea of infancy requiring lifelong total parenteral
nutrition. Duodenal biopsy at age 2 months showed villous atrophy, but
subsequent biopsies were normal. She had several episodes of line sepsis
and pancytopenia on 1 hospitalization. Physical exam at age 3 years
found facial dysmorphism with prominent forehead and cheeks, broad nasal
root, hypertelorism, and mental retardation. Her hair was brittle with
trichorrhexis nodosa in nearly all hair shafts. Hepatomegaly was noted,
and liver biopsy showed cirrhosis. Laboratory studies showed mild
anemia, leukopenia, and thrombocytopenia. At the time of the report, she
was awaiting liver transplant.
Barabino et al. (2004) reported a girl who developed chronic diarrhea at
15 days of age. Total parenteral nutrition was started and then
discontinued at 1 year. She had the typical facial features, hair
abnormalities, and intestinal findings consistent with what the authors
termed 'syndromic diarrhea.' At age 17 years, she showed severe growth
delay but normal pubertal development. She had mild mental impairment,
intermittent diarrhea, and frequent upper respiratory infections.
Intestinal histology had improved. An older sister died during infancy
from unexplained diarrhea.
Dweikat et al. (2007) reported a female infant, born of first-cousin
parents, with hemochromatosis, intractable diarrhea, dysmorphic
features, and hair abnormality. She was born at term and had a normal
neonatal course. Failure to thrive was noted at age 1 month. Watery
diarrhea began at age 50 days and continued despite dietary changes and
3 weeks of bowel rest. Physical exam at age 3 months showed decreased
physical growth, sparse, thin, curly hair, hypertelorism, broad nose,
prominent eyes, and umbilical and bilateral inguinal hernias. Laboratory
studies showed abnormally increased liver enzymes and increased serum
iron content. Liver biopsy showed edema, fibrosis, and iron deposition.
Hypermethioninemia was not present. Psychomotor development was normal
until her death at age 10 months from intractable diarrhea. Dweikat et
al. (2007) noted the phenotypic similarities to the patients reported by
Stankler et al. (1982) and Verloes et al. (1997).
Fabre et al. (2007) reported 2 unrelated male infants with THE syndrome.
Both developed intractable watery diarrhea requiring total parenteral
nutrition at ages 1 and 3 months, respectively. Both also had facial
dysmorphism with large forehead, hypertelorism, and broad nasal root,
and trichorrhexis nodosa. Other common features included hepatic
cirrhosis and mild humoral immunodeficiency. In 1 child, duodenal biopsy
showed total villous atrophy at 1 month, and subsequent testing at 20
months showed moderate villous atrophy. Fabre et al. (2007) suggested
that THE syndrome and the 'syndromic diarrhea' described by Barabino et
al. (2004) are the same disease entity.
Hartley et al. (2010) studied 12 affected children from 11 families with
THES, 8 of which were consanguineous. All children exhibited the
characteristic facial features and trichorrhexis nodosa of the hair on
microscopy. There was a high incidence of preterm delivery and
intrauterine growth retardation. Diarrhea developed between 2 weeks of
age and 7 months, and all children required parenteral nutrition in
infancy; in 2 patients, parenteral nutrition could be discontinued due
to improvement in diarrhea. Histologic examination of serially obtained
jejunal biopsy specimens suggested that the villous atrophy can improve
with age and the inflammatory infiltrate is not consistent. Serum
immunoglobulin levels were low in 11 of the 12 children, requiring
supplementation during the neonatal period. Cardiac anomalies were
present in 5 children, including aortic insufficiency in 2, peripheral
pulmonary stenosis in 1, ventricular septal defect in 1, and tetralogy
of Fallot in 1. Developmental delay was present in all 7 children who
were old enough to be assessed. Previously unrecognized platelet
abnormalities were identified in 6 of the children, with large platelets
observed in 5 and thrombocytosis in 4; transmission electron microscopy
revealed reduced platelet alpha-granules, unusual stimulated
alpha-granule content release, abnormal lipid inclusions, abnormal
platelet canalicular system, and reduced number of microtubules.
MAPPING
Hartley et al. (2010) performed genomewide linkage analysis in 8
children with trichohepatoenteric syndrome from consanguineous families
and identified 3 extended regions of homozygosity shared by all 8
children. Further genotyping in all available family members using
microsatellite markers excluded 2 of the regions and confirmed linkage
to chromosome 5q14.3-q21.2, defining a 12.9-Mb interval between markers
D5S815 and D5S409. Multipoint linkage analysis yielded a maximum lod
score of 5.8 (theta = 0) at D5S1462.
MOLECULAR GENETICS
In 12 children from 11 unrelated families with trichohepatoenteric
syndrome mapping to chromosome 5q14.3-q21.2, Hartley et al. (2010)
identified homozygosity or compound heterozygosity for 9 different
mutations in the candidate gene TTC37 (see, e.g.,
614589.0001-614589.0005). All mutations segregated with disease status
in the family, and none were detected in at least 350 ethnically matched
South Asian and Caucasian control chromosomes.
Fabre et al. (2011) analyzed the TTC37 gene in 12 THES patients from 11
families, including the 2 boys originally reported by Fabre et al.
(2007), and identified homozygosity or compound heterozygosity for 11
different mutations in 9 of the patients (see, e.g.,
614589.0006-614589.0008). The phenotypes of the 3 female patients in
whom no mutation in TTC37 was detected were reevaluated and confirmed as
being typical THES, suggesting that at least 1 other gene may be
implicated in the disease.
*FIELD* RF
1. Barabino, A. V.; Torrente, F.; Castellano, E.; Erba, D.; Calvi,
A.; Gandullia, P.: 'Syndromic diarrhea' may have better outcome than
previously reported. J. Pediat. 144: 553-554, 2004. Note: Erratum:
J. Pediat. 144: 838 only, 2004.
2. Dweikat, I.; Sultan, M.; Maraqa, N.; Hindi, T.; Abu-Rmeileh, S.;
Abu-Libdeh, B.: Tricho-hepato-enteric syndrome: a case of hemochromatosis
with intractable diarrhea, dysmorphic features, and hair abnormality Am.
J. Med. Genet. 143A: 581-583, 2007.
3. Fabre, A.; Andre, N.; Breton, A.; Broue, P.; Badens, C.; Roquelaure,
B.: Intractable diarrhea with 'phenotypic anomalies' and tricho-hepato-enteric
syndrome: two names for the same disorder. Am. J. Med. Genet. 143A:
584-588, 2007.
4. Fabre, A.; Martinez-Vinson, C.; Roquelaure, B.; Missirian, C.;
Andre, N.; Breton, A.; Lachaux, A.; Odul, E.; Colomb, V.; Lemale,
J.; Cezard, J.-P.; Goulet, O.; Sarles, J.; Levy, N.; Badens, C.:
Novel mutations in TTC37 associated with tricho-hepato-enteric syndrome. Hum.
Mutat. 32: 277-281, 2011.
5. Girault, D.; Goulet, O.; Le Deist, F.; Brousse, N.; Colomb, V.;
Cesarini, J.-P.; de Potter, S.; Canioni, D.; Griscelli, C.; Fischer,
A.; Ricour, C.: Intractable infant diarrhea associated with phenotypic
abnormalities and immunodeficiency. J. Pediat. 125: 36-42, 1994.
6. Goulet, O. J.; Brousse, N.; Canioni, D.; Walker-Smith, J. A.; Schmitz,
J.; Phillips, A. D.: Syndrome of intractable diarrhoea with persistent
villous atrophy in early childhood: a clinicopathological survey of
47 cases. J. Pediat. Gastroent. Nutr. 26: 151-161, 1998.
7. Hartley, J. L.; Zachos, N. C.; Dawood, B.; Donowitz, M.; Forman,
J.; Pollitt, R. J.; Morgan, N. V.; Tee, L.; Gissen, P.; Kahr, W. H.
A.; Knisely, A. S.; Watson, S.; Chitayat, D.; Booth, I. W.; Protheroe,
S.; Murphy, S.; De Vries, E.; Kelly, D. A.; Maher, E. R.: Mutations
in TTC37 cause trichohepatoenteric syndrome (phenotypic diarrhea of
infancy). Gastroenterology 138: 2388-2398, 2010.
8. Landers, M. C.; Schroeder, T. L.: Intractable diarrhea of infancy
with facial dysmorphism, trichorrhexis nodosa, and cirrhosis. Pediat.
Derm. 20: 432-435, 2003.
9. Stankler, L.; Lloyd, D.; Pollitt, R. J.; Gray, E. S.; Thom, H.;
Russell, G.: Unexplained diarrhoea and failure to thrive in 2 siblings
with unusual facies and abnormal scalp hair shafts: a new syndrome. Arch.
Dis. Child. 57: 212-216, 1982.
10. Verloes, A.; Lombet, J.; Lambert, Y.; Hubert, A.-F.; Deprez, M.;
Fridman, V.; Gosseye, S.; Rigo, J.; Sokal, E.: Tricho-hepato-enteric
syndrome: further delineation of a distinct syndrome with neonatal
hemochromatosis phenotype, intractable diarrhea, and hair anomalies. Am.
J. Med. Genet. 68: 391-395, 1997.
*FIELD* CS
INHERITANCE:
Autosomal recessive
GROWTH:
[Height];
Decreased height;
[Weight];
Low birth weight;
[Other];
Failure to thrive;
Intrauterine growth retardation (IUGR)
HEAD AND NECK:
[Face];
Prominent forehead;
Square forehead;
Prominent cheeks;
Flat supraorbital ridges;
Long philtrum;
[Ears];
Low-set ears;
Simple ears;
Small ears;
[Eyes];
Hypertelorism;
Prominent eyes;
Downslanting palpebral fissures;
[Nose];
Flat, broad nose;
Upturned nose;
[Mouth];
Small mouth: Large mouth;
Cleft uvula
CARDIOVASCULAR:
[Heart];
Aortic insufficiency (in some patients);
Tetralogy of Fallot (rare);
Ventricular septal defect (rare);
Pulmonary stenosis (rare)
ABDOMEN:
[Liver];
Cholestatic jaundice;
Hepatomegaly;
Cirrhosis;
Progressive liver failure;
Increased iron in hepatocytes;
Liver fibrosis with nodular regeneration, cholestasis, ductular proliferation,
and iron deposition;
[Pancreas];
Islet cell hyperplasia;
[Gastrointestinal];
Diarrhea, secretory, severe;
Villous atrophy
GENITOURINARY:
[Kidneys];
Cortical microcysts
SKIN, NAILS, HAIR:
[Hair];
Thin, sparse hair;
Curly hair;
Brittle hair;
Woolly hair;
Trichorrhexis nodosa
NEUROLOGIC:
[Central nervous system];
Mental impairment
METABOLIC FEATURES:
Neonatal hemochromatosis
HEMATOLOGY:
Thrombocytosis (in some patients);
Large platelets (in some patients)
IMMUNOLOGY:
Defective antibody response;
Defective antigen-specific skin response
PRENATAL MANIFESTATIONS:
Intrauterine growth retardation;
[Amniotic fluid];
Polyhydramnios;
[Placenta and umbilical cord];
Large placenta
LABORATORY ABNORMALITIES:
Hypoalbuminemia;
Galactosuria without galactosemia;
Hypermethioninemia, progressive;
Increased serum methionine (reported in 2 cases);
Abnormal serum liver enzyme levels;
Elevated ferritin;
Decreased transferrin Increased serum iron
MISCELLANEOUS:
Onset usually in first month of life;
Patients need lifelong total parenteral nutrition;
Often fatal due in infancy due to intractable diarrhea
MOLECULAR BASIS:
Caused by mutation in the tetratricopeptide repeat domain 37 gene
(TTC37, 614589.0001)
*FIELD* CN
Marla J. F. O'Neill - updated: 05/01/2012
Kelly A. Przylepa - revised: 3/8/2008
Cassandra L. Kniffin - revised: 4/10/2007
*FIELD* CD
John F. Jackson: 6/15/1995
*FIELD* ED
joanna: 05/01/2012
joanna: 1/25/2010
joanna: 2/19/2009
joanna: 3/8/2008
ckniffin: 4/10/2007
*FIELD* CN
Marla J. F. O'Neill - updated: 04/27/2012
Marla J. F. O'Neill - updated: 1/25/2010
Marla J. F. O'Neill - updated: 1/12/2010
Deborah L. Stone - updated: 8/26/2002
*FIELD* CD
Victor A. McKusick: 6/3/1986
*FIELD* ED
carol: 04/27/2012
wwang: 2/19/2010
carol: 1/25/2010
carol: 1/12/2010
wwang: 4/16/2007
ckniffin: 4/10/2007
terry: 4/19/2005
carol: 8/26/2002
mimadm: 2/19/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 6/3/1986
*RECORD*
*FIELD* NO
222470
*FIELD* TI
#222470 TRICHOHEPATOENTERIC SYNDROME 1; THES1
;;THE SYNDROME;;
DIARRHEA, SYNDROMIC;;
read moreDIARRHEA, FATAL INFANTILE, WITH TRICHORRHEXIS NODOSA
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
trichohepatoenteric syndrome-1 (THES1) is caused by homozygous or
compound heterozygous mutation in the TTC37 gene (614589) on chromosome
5q15.
DESCRIPTION
Although the spectrum of phenotypic expression in trichohepatoenteric
syndrome (THES) is broad, the characteristic features include
intrauterine growth retardation, woolly hair, facial dysmorphism,
intractable diarrhea in infancy requiring total parenteral nutrition,
and immunodepression. Hepatic involvement contributes to the poor
prognosis of affected patients (summary by Fabre et al., 2007).
- Genetic Heterogeneity of Trichohepatoenteric Syndrome
Trichohepatoenteric syndrome-2 (THES2; 614602) is caused by mutation in
the SKIV2L gene (600478) on chromosome 6p21.3.
CLINICAL FEATURES
Stankler et al. (1982) reported a seemingly 'new,' presumably autosomal
recessive disorder in a sister and brother who died at 33 and 87 days of
age, respectively, with severe unexplained diarrhea. Both were of low
birth weight for dates and had large, low-set, simple ears, flat nasal
bridge, and large mouth. Both had woolly, easily removed black hair
showing an abnormality the authors dubbed 'trichorrhexis blastysis.' By
scanning microscopy, the hairs showed projections at multiple sites
arising from the convex surface of a kinked hair and suggesting buds
(Gr. blastosis = bud). The hair had a low content of cystine and an
abnormal content of several other amino acids. Both parents had normal
hair microscopically and chemically. In both sibs, the diarrhea began in
the third week of life and was preceded by excoriated buttocks. Both had
galactosuria without galactosemia. At autopsy both had hepatic fibrosis
and hemosiderosis and islet cell hyperplasia. Menkes disease (309400)
and argininosuccinic aciduria (207900), which have somewhat similar
findings in the hair, were excluded by chemical tests.
Girault et al. (1994) reported 8 children with severe secretory diarrhea
beginning in the first 6 months of life (less than 1 month in 6 cases).
All were small for gestational age and had facial dysmorphism and
woolly, easily removable hair with trichorrhexis nodosa. Two children
were from consanguineous marriages. Diarrhea was refractive to therapy,
including bowel rest. All patients had jejunal biopsies that showed
total or subtotal villous atrophy, defective antigen-specific skin
tests, and defective antibody responses despite normal serum
immunoglobulin levels. Two patients had hepatic cirrhosis, and 3
children had mental retardation. At the time of the report, 5 patients
had died between the ages of 2 and 5 years, 2 were fed enterally, and 1
continued to receive total parenteral nutrition. Barabino et al. (2004)
reported follow-up of the patient dependent on parenteral nutrition
reported by Girault et al. (1994). At age 6 years, she achieved
intestinal autonomy with discontinuation of the parenteral nutrition. At
age 14 years, she had mild psychomotor and pubertal delay. She had
chronic malabsorptive diarrhea, hypoalbuminemia, iron-deficiency anemia,
osteoporosis, and impaired intestinal permeability. Immunologic defect
was still present, but no other infections were recorded.
Verloes et al. (1997) used the term 'tricho-hepato-enteric syndrome' to
describe the disorder in a brother and sister who were noted prenatally
to have intrauterine growth retardation, hydramnios, and placental
hyperplasia. Both had intractable diarrhea with normal histologic and
enzymologic studies. Facial anomalies included hypertelorism, upturned
noses, small mouths, and low-set ears. Hair texture and pattern were
abnormal. Neurologically, they appeared grossly normal. The sister was
noted to have cholestatic jaundice and hepatomegaly at 2 months of age,
whereas the brother was noted to have hepatic dysfunction at birth with
a high alpha-fetoprotein level. He also had mild and delayed
hypermethioninemia. Both died at about 6 months of age. Pathologic
examination of both children showed a similar pattern of multivisceral
iron deposition compatible with a diagnosis of neonatal hemochromatosis,
although the clinical picture of an asymptomatic neonatal period was
unusual.
Goulet et al. (1998) studied the clinical and histopathologic features
of 47 infants with intractable diarrhea and villous atrophy of varying
degrees, dividing them into 2 groups, with or without lamina propria
mononuclear cell infiltration. Of the 18 patients in the latter group, 8
had phenotypic abnormalities including facial dysmorphism and abnormal
hair; 6 of the 8 patients had previously been reported by Girault et al.
(1994).
Landers and Schroeder (2003) reported a 3-year-old girl with severe
intractable diarrhea of infancy requiring lifelong total parenteral
nutrition. Duodenal biopsy at age 2 months showed villous atrophy, but
subsequent biopsies were normal. She had several episodes of line sepsis
and pancytopenia on 1 hospitalization. Physical exam at age 3 years
found facial dysmorphism with prominent forehead and cheeks, broad nasal
root, hypertelorism, and mental retardation. Her hair was brittle with
trichorrhexis nodosa in nearly all hair shafts. Hepatomegaly was noted,
and liver biopsy showed cirrhosis. Laboratory studies showed mild
anemia, leukopenia, and thrombocytopenia. At the time of the report, she
was awaiting liver transplant.
Barabino et al. (2004) reported a girl who developed chronic diarrhea at
15 days of age. Total parenteral nutrition was started and then
discontinued at 1 year. She had the typical facial features, hair
abnormalities, and intestinal findings consistent with what the authors
termed 'syndromic diarrhea.' At age 17 years, she showed severe growth
delay but normal pubertal development. She had mild mental impairment,
intermittent diarrhea, and frequent upper respiratory infections.
Intestinal histology had improved. An older sister died during infancy
from unexplained diarrhea.
Dweikat et al. (2007) reported a female infant, born of first-cousin
parents, with hemochromatosis, intractable diarrhea, dysmorphic
features, and hair abnormality. She was born at term and had a normal
neonatal course. Failure to thrive was noted at age 1 month. Watery
diarrhea began at age 50 days and continued despite dietary changes and
3 weeks of bowel rest. Physical exam at age 3 months showed decreased
physical growth, sparse, thin, curly hair, hypertelorism, broad nose,
prominent eyes, and umbilical and bilateral inguinal hernias. Laboratory
studies showed abnormally increased liver enzymes and increased serum
iron content. Liver biopsy showed edema, fibrosis, and iron deposition.
Hypermethioninemia was not present. Psychomotor development was normal
until her death at age 10 months from intractable diarrhea. Dweikat et
al. (2007) noted the phenotypic similarities to the patients reported by
Stankler et al. (1982) and Verloes et al. (1997).
Fabre et al. (2007) reported 2 unrelated male infants with THE syndrome.
Both developed intractable watery diarrhea requiring total parenteral
nutrition at ages 1 and 3 months, respectively. Both also had facial
dysmorphism with large forehead, hypertelorism, and broad nasal root,
and trichorrhexis nodosa. Other common features included hepatic
cirrhosis and mild humoral immunodeficiency. In 1 child, duodenal biopsy
showed total villous atrophy at 1 month, and subsequent testing at 20
months showed moderate villous atrophy. Fabre et al. (2007) suggested
that THE syndrome and the 'syndromic diarrhea' described by Barabino et
al. (2004) are the same disease entity.
Hartley et al. (2010) studied 12 affected children from 11 families with
THES, 8 of which were consanguineous. All children exhibited the
characteristic facial features and trichorrhexis nodosa of the hair on
microscopy. There was a high incidence of preterm delivery and
intrauterine growth retardation. Diarrhea developed between 2 weeks of
age and 7 months, and all children required parenteral nutrition in
infancy; in 2 patients, parenteral nutrition could be discontinued due
to improvement in diarrhea. Histologic examination of serially obtained
jejunal biopsy specimens suggested that the villous atrophy can improve
with age and the inflammatory infiltrate is not consistent. Serum
immunoglobulin levels were low in 11 of the 12 children, requiring
supplementation during the neonatal period. Cardiac anomalies were
present in 5 children, including aortic insufficiency in 2, peripheral
pulmonary stenosis in 1, ventricular septal defect in 1, and tetralogy
of Fallot in 1. Developmental delay was present in all 7 children who
were old enough to be assessed. Previously unrecognized platelet
abnormalities were identified in 6 of the children, with large platelets
observed in 5 and thrombocytosis in 4; transmission electron microscopy
revealed reduced platelet alpha-granules, unusual stimulated
alpha-granule content release, abnormal lipid inclusions, abnormal
platelet canalicular system, and reduced number of microtubules.
MAPPING
Hartley et al. (2010) performed genomewide linkage analysis in 8
children with trichohepatoenteric syndrome from consanguineous families
and identified 3 extended regions of homozygosity shared by all 8
children. Further genotyping in all available family members using
microsatellite markers excluded 2 of the regions and confirmed linkage
to chromosome 5q14.3-q21.2, defining a 12.9-Mb interval between markers
D5S815 and D5S409. Multipoint linkage analysis yielded a maximum lod
score of 5.8 (theta = 0) at D5S1462.
MOLECULAR GENETICS
In 12 children from 11 unrelated families with trichohepatoenteric
syndrome mapping to chromosome 5q14.3-q21.2, Hartley et al. (2010)
identified homozygosity or compound heterozygosity for 9 different
mutations in the candidate gene TTC37 (see, e.g.,
614589.0001-614589.0005). All mutations segregated with disease status
in the family, and none were detected in at least 350 ethnically matched
South Asian and Caucasian control chromosomes.
Fabre et al. (2011) analyzed the TTC37 gene in 12 THES patients from 11
families, including the 2 boys originally reported by Fabre et al.
(2007), and identified homozygosity or compound heterozygosity for 11
different mutations in 9 of the patients (see, e.g.,
614589.0006-614589.0008). The phenotypes of the 3 female patients in
whom no mutation in TTC37 was detected were reevaluated and confirmed as
being typical THES, suggesting that at least 1 other gene may be
implicated in the disease.
*FIELD* RF
1. Barabino, A. V.; Torrente, F.; Castellano, E.; Erba, D.; Calvi,
A.; Gandullia, P.: 'Syndromic diarrhea' may have better outcome than
previously reported. J. Pediat. 144: 553-554, 2004. Note: Erratum:
J. Pediat. 144: 838 only, 2004.
2. Dweikat, I.; Sultan, M.; Maraqa, N.; Hindi, T.; Abu-Rmeileh, S.;
Abu-Libdeh, B.: Tricho-hepato-enteric syndrome: a case of hemochromatosis
with intractable diarrhea, dysmorphic features, and hair abnormality Am.
J. Med. Genet. 143A: 581-583, 2007.
3. Fabre, A.; Andre, N.; Breton, A.; Broue, P.; Badens, C.; Roquelaure,
B.: Intractable diarrhea with 'phenotypic anomalies' and tricho-hepato-enteric
syndrome: two names for the same disorder. Am. J. Med. Genet. 143A:
584-588, 2007.
4. Fabre, A.; Martinez-Vinson, C.; Roquelaure, B.; Missirian, C.;
Andre, N.; Breton, A.; Lachaux, A.; Odul, E.; Colomb, V.; Lemale,
J.; Cezard, J.-P.; Goulet, O.; Sarles, J.; Levy, N.; Badens, C.:
Novel mutations in TTC37 associated with tricho-hepato-enteric syndrome. Hum.
Mutat. 32: 277-281, 2011.
5. Girault, D.; Goulet, O.; Le Deist, F.; Brousse, N.; Colomb, V.;
Cesarini, J.-P.; de Potter, S.; Canioni, D.; Griscelli, C.; Fischer,
A.; Ricour, C.: Intractable infant diarrhea associated with phenotypic
abnormalities and immunodeficiency. J. Pediat. 125: 36-42, 1994.
6. Goulet, O. J.; Brousse, N.; Canioni, D.; Walker-Smith, J. A.; Schmitz,
J.; Phillips, A. D.: Syndrome of intractable diarrhoea with persistent
villous atrophy in early childhood: a clinicopathological survey of
47 cases. J. Pediat. Gastroent. Nutr. 26: 151-161, 1998.
7. Hartley, J. L.; Zachos, N. C.; Dawood, B.; Donowitz, M.; Forman,
J.; Pollitt, R. J.; Morgan, N. V.; Tee, L.; Gissen, P.; Kahr, W. H.
A.; Knisely, A. S.; Watson, S.; Chitayat, D.; Booth, I. W.; Protheroe,
S.; Murphy, S.; De Vries, E.; Kelly, D. A.; Maher, E. R.: Mutations
in TTC37 cause trichohepatoenteric syndrome (phenotypic diarrhea of
infancy). Gastroenterology 138: 2388-2398, 2010.
8. Landers, M. C.; Schroeder, T. L.: Intractable diarrhea of infancy
with facial dysmorphism, trichorrhexis nodosa, and cirrhosis. Pediat.
Derm. 20: 432-435, 2003.
9. Stankler, L.; Lloyd, D.; Pollitt, R. J.; Gray, E. S.; Thom, H.;
Russell, G.: Unexplained diarrhoea and failure to thrive in 2 siblings
with unusual facies and abnormal scalp hair shafts: a new syndrome. Arch.
Dis. Child. 57: 212-216, 1982.
10. Verloes, A.; Lombet, J.; Lambert, Y.; Hubert, A.-F.; Deprez, M.;
Fridman, V.; Gosseye, S.; Rigo, J.; Sokal, E.: Tricho-hepato-enteric
syndrome: further delineation of a distinct syndrome with neonatal
hemochromatosis phenotype, intractable diarrhea, and hair anomalies. Am.
J. Med. Genet. 68: 391-395, 1997.
*FIELD* CS
INHERITANCE:
Autosomal recessive
GROWTH:
[Height];
Decreased height;
[Weight];
Low birth weight;
[Other];
Failure to thrive;
Intrauterine growth retardation (IUGR)
HEAD AND NECK:
[Face];
Prominent forehead;
Square forehead;
Prominent cheeks;
Flat supraorbital ridges;
Long philtrum;
[Ears];
Low-set ears;
Simple ears;
Small ears;
[Eyes];
Hypertelorism;
Prominent eyes;
Downslanting palpebral fissures;
[Nose];
Flat, broad nose;
Upturned nose;
[Mouth];
Small mouth: Large mouth;
Cleft uvula
CARDIOVASCULAR:
[Heart];
Aortic insufficiency (in some patients);
Tetralogy of Fallot (rare);
Ventricular septal defect (rare);
Pulmonary stenosis (rare)
ABDOMEN:
[Liver];
Cholestatic jaundice;
Hepatomegaly;
Cirrhosis;
Progressive liver failure;
Increased iron in hepatocytes;
Liver fibrosis with nodular regeneration, cholestasis, ductular proliferation,
and iron deposition;
[Pancreas];
Islet cell hyperplasia;
[Gastrointestinal];
Diarrhea, secretory, severe;
Villous atrophy
GENITOURINARY:
[Kidneys];
Cortical microcysts
SKIN, NAILS, HAIR:
[Hair];
Thin, sparse hair;
Curly hair;
Brittle hair;
Woolly hair;
Trichorrhexis nodosa
NEUROLOGIC:
[Central nervous system];
Mental impairment
METABOLIC FEATURES:
Neonatal hemochromatosis
HEMATOLOGY:
Thrombocytosis (in some patients);
Large platelets (in some patients)
IMMUNOLOGY:
Defective antibody response;
Defective antigen-specific skin response
PRENATAL MANIFESTATIONS:
Intrauterine growth retardation;
[Amniotic fluid];
Polyhydramnios;
[Placenta and umbilical cord];
Large placenta
LABORATORY ABNORMALITIES:
Hypoalbuminemia;
Galactosuria without galactosemia;
Hypermethioninemia, progressive;
Increased serum methionine (reported in 2 cases);
Abnormal serum liver enzyme levels;
Elevated ferritin;
Decreased transferrin Increased serum iron
MISCELLANEOUS:
Onset usually in first month of life;
Patients need lifelong total parenteral nutrition;
Often fatal due in infancy due to intractable diarrhea
MOLECULAR BASIS:
Caused by mutation in the tetratricopeptide repeat domain 37 gene
(TTC37, 614589.0001)
*FIELD* CN
Marla J. F. O'Neill - updated: 05/01/2012
Kelly A. Przylepa - revised: 3/8/2008
Cassandra L. Kniffin - revised: 4/10/2007
*FIELD* CD
John F. Jackson: 6/15/1995
*FIELD* ED
joanna: 05/01/2012
joanna: 1/25/2010
joanna: 2/19/2009
joanna: 3/8/2008
ckniffin: 4/10/2007
*FIELD* CN
Marla J. F. O'Neill - updated: 04/27/2012
Marla J. F. O'Neill - updated: 1/25/2010
Marla J. F. O'Neill - updated: 1/12/2010
Deborah L. Stone - updated: 8/26/2002
*FIELD* CD
Victor A. McKusick: 6/3/1986
*FIELD* ED
carol: 04/27/2012
wwang: 2/19/2010
carol: 1/25/2010
carol: 1/12/2010
wwang: 4/16/2007
ckniffin: 4/10/2007
terry: 4/19/2005
carol: 8/26/2002
mimadm: 2/19/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988
reenie: 6/3/1986
MIM
614589
*RECORD*
*FIELD* NO
614589
*FIELD* TI
*614589 TETRATRICOPEPTIDE REPEAT DOMAIN-CONTAINING PROTEIN 37; TTC37
;;KIAA0372
*FIELD* TX
read more
CLONING
By sequencing clones obtained from a size-fractionated human brain cDNA
library, Nagase et al. (1997) cloned TTC37, which they designated
KIAA0372. The deduced protein contains 1,564 amino acids. RT-PCR
analysis detected high expression in placenta and low expression in
kidney and ovary. Little to no expression was detected in all other
tissues examined.
Fabre et al. (2011) assessed quantitative expression of TTC37 in a panel
of 48 different tissues and found that TTC37 is widely expressed, with
the highest levels observed in vascular tissues, lymph node, pituitary,
lung, and intestine. They found no expression in liver.
MAPPING
By radiation hybrid analysis, Nagase et al. (1997) mapped the TTC37 gene
to chromosome 5.
Amberger (2012) mapped the TTC37 gene to chromosome 5q15 based on an
alignment of the TTC37 sequence (GenBank GENBANK AB002370) with the
genomic sequence (GRCh37).
MOLECULAR GENETICS
In 12 children from 11 unrelated families with trichohepatoenteric
syndrome mapping to chromosome 5q14.3-q21.2 (THES1; 222470), Hartley et
al. (2010) identified homozygosity or compound heterozygosity for 9
different mutations in the candidate gene TTC37 (see, e.g.,
614589.0001-614589.0005). Preliminary studies in 5 patients of
enterocyte brush-border ion transporter proteins, including NHE2
(SLC9A2; 600530), NHE3 (SLC9A3; 182307), NIS (SLC5A5; 601843), AQP7
(602974), and H/K ATPase (see ATP4A, 137216), demonstrated reduced
expression or mislocalization compared to controls. Hartley et al.
(2010) suggested that the multisystem effect of TTC37 mutations might be
due to abnormal stability and/or intracellular localization of TTC37
target proteins.
Fabre et al. (2011) analyzed the TTC37 gene in 12 THES patients from 11
families and identified homozygosity or compound heterozygosity for 11
different mutations in 9 of the patients (see, e.g.,
614589.0006-614589.0008).
*FIELD* AV
.0001
TRICHOHEPATOENTERIC SYNDROME 1
TTC37, TRP936TER
In 4 children with trichohepatoenteric syndrome (THES1; 222470),
including 2 sisters from an Indian family and 2 boys from 2 unrelated
consanguineous Pakistani families, Hartley et al. (2010) identified
homozygosity for a 2808G-A transition in exon 28 of the TTC37 gene,
resulting in a trp936-to-ter (W936X) substitution. SNP haplotypes in the
affected individuals were identical over a 974-kb region containing
TTC37, from SNP dbSNP rs255375 to SNP dbSNP rs34897, consistent with a
founder mutation. The mutation segregated with disease in each family
and was not found in at least 350 ethnically matched South Asian and
Caucasian control chromosomes. All 4 children had intrauterine growth
retardation, villous atrophy on jejunal biopsies, and trichorrhexis
nodosa. The Indian sisters, who both exhibited thrombocytosis and large
platelets, died at 6 months of age; 1 sib also had a ventricular septal
defect. The Pakistani boys had no platelet abnormalities or cardiac
defects; 1 died at 8 years of age, whereas the other was alive at 1 year
of age. Analysis of enterocyte brush-border ion transporter proteins in
1 of the patients demonstrated that apical expression of AQP7 (602974)
was absent, suggesting that TTC37 may regulate expression of AQP7.
.0002
TRICHOHEPATOENTERIC SYNDROME 1
TTC37, IVS28, G-A, -2
In an 11-year-old Pakistani girl and an unrelated 3.5-year-old Pakistani
boy with trichohepatoenteric syndrome-1 (222470), both from
consanguineous families, Hartley et al. (2010) identified homozygosity
for a G-A transition at -2 in intron 28 (2779-2G-A) in the TTC37 gene,
predicted to cause skipping of exon 29 and premature termination. The
mutation segregated with disease in both families and was not found in
at least 350 ethnically matched South Asian and Caucasian control
chromosomes. Both children had intrauterine growth retardation,
characteristic facial dysmorphology, villous atrophy on jejunal
biopsies, trichorrhexis nodosa, and low immunoglobulins, and both
exhibited developmental delay. In addition, the girl had mild aortic
insufficiency and the boy had peripheral pulmonary stenosis. Analysis of
enterocyte brush-border ion transporter proteins in the 2 patients
demonstrated that apical expression of H/K ATPase (see ATP4A, 137216)
was reduced and that of AQP7 (602974) was absent, and there was
mislocalization of NHE2 (SLC9A2; 600530), NHE3 (SLC9A3; 182307), and NIS
(SLC5A5; 601843) compared to controls, suggesting that the multisystem
effect of TTC37 mutations might be due to abnormal stability and/or
intracellular localization of TTC37 target proteins.
.0003
TRICHOHEPATOENTERIC SYNDROME 1
TTC37, IVS17, 1-BP DEL, G, +1
In a 2.5-year-old girl from a consanguineous Kurdish family with
trichohepatoenteric syndrome-1 (222470), Hartley et al. (2010)
identified homozygosity for a 1-bp deletion in intron 17 (1632+1delG) of
the TTC37 gene, producing a frameshift predicted to result in a
premature termination codon. The mutation segregated with disease in the
family and was not found in at least 350 ethnically matched South Asian
and Caucasian control chromosomes. Analysis of enterocyte brush-border
ion transporter proteins in the patient demonstrated that apical
expression of H/K ATPase (see ATP4A, 137216) was reduced and that of
AQP7 (602974) was absent.
.0004
TRICHOHEPATOENTERIC SYNDROME 1
TTC37, GLN147TER
In a 13-year-old Italian girl with trichohepatoenteric syndrome-1
(222470), Hartley et al. (2010) identified compound heterozygosity for a
439C-T transition in exon 8 of the TTC37 gene, resulting in a
gln147-to-ter (Q147X) substitution, and a 2251C-T transition in exon 21,
resulting in a gln751-to-ter (Q751X; 614589.0005) substitution. The
mutations segregated with disease in the family and were not found in at
least 350 ethnically matched South Asian and Caucasian control
chromosomes. Features in this patient included intrauterine growth
retardation, characteristic facial dysmorphology, villous atrophy on
jejunal biopsy, trichorrhexis nodosa, diffuse hypopigmentation of the
skin, low immunoglobulins, aortic insufficiency, and developmental
delay.
.0005
TRICHOHEPATOENTERIC SYNDROME 1
TTC37, GLN751TER
See 614589.0004 and Hartley et al. (2010).
.0006
TRICHOHEPATOENTERIC SYNDROME 1
TTC37, IVS23, G-C, +1
In a North African patient with trichohepatoenteric syndrome (222470),
Fabre et al. (2011) identified homozygosity for a G-C transversion in
intron 23 (2515+1G-C) of the TTC37 gene. Direct sequencing of RNA
transcripts from lymphoblastoid cells revealed that the mutation caused
a frameshift and creation of a premature termination codon. The mutation
was found in heterozygosity in the unaffected parents.
.0007
TRICHOHEPATOENTERIC SYNDROME 1
TTC37, IVS24, 5-BP DEL, -7
In a French patient with trichohepatoenteric syndrome-1 (222470), Fabre
et al. (2011) identified compound heterozygosity for a 5-bp deletion in
IVS24 (2577-7_-3delTTTTT) of the TTC37 gene, and a G-C transversion in
IVS42 (4620+1G-C; 614589.0008). Direct sequencing of RNA transcripts
from lymphoblastoid cells revealed that the 2577-7_-3delTTTT mutation
caused skipping of exon 25, resulting in the deletion of 19 in-frame
amino acids, whereas the 4620+1G-C mutation caused cryptic splice
activation in exon 42, resulting in alternative splicing and the
replacement of the 41 terminal amino acids by 61 others.
.0008
TRICHOHEPATOENTERIC SYNDROME 1
TTC37, IVS42, G-C, +1
See 614589.0007 and Fabre et al. (2011).
*FIELD* RF
1. Amberger, J. S.: Personal Communication. Baltimore, Md. 4/24/2012.
2. Fabre, A.; Martinez-Vinson, C.; Roquelaure, B.; Missirian, C.;
Andre, N.; Breton, A.; Lachaux, A.; Odul, E.; Colomb, V.; Lemale,
J.; Cezard, J.-P.; Goulet, O.; Sarles, J.; Levy, N.; Badens, C.:
Novel mutations in TTC37 associated with tricho-hepato-enteric syndrome. Hum.
Mutat. 32: 277-281, 2011.
3. Hartley, J. L.; Zachos, N. C.; Dawood, B.; Donowitz, M.; Forman,
J.; Pollitt, R. J.; Morgan, N. V.; Tee, L.; Gissen, P.; Kahr, W. H.
A.; Knisely, A. S.; Watson, S.; Chitayat, D.; Booth, I. W.; Protheroe,
S.; Murphy, S.; De Vries, E.; Kelly, D. A.; Maher, E. R.: Mutations
in TTC37 cause trichohepatoenteric syndrome (phenotypic diarrhea of
infancy). Gastroenterology 138: 2388-2398, 2010.
4. Nagase, T.; Ishikawa, K.; Nakajima, D.; Ohira, M.; Seki, N.; Miyajima,
N.; Tanaka, A.; Kotani, H.; Nomura, N.; Ohara, O.: Prediction of
the coding sequences of unidentified human genes. VII. The complete
sequences of 100 new cDNA clones from brain which can code for large
proteins in vitro. DNA Res. 4: 141-150, 1997.
*FIELD* CN
Marla J. F. O'Neill - updated: 4/27/2012
*FIELD* CD
Joanna S. Amberger: 4/24/2012
*FIELD* ED
carol: 09/11/2013
mgross: 2/26/2013
carol: 4/27/2012
mgross: 4/24/2012
joanna: 4/24/2012
*RECORD*
*FIELD* NO
614589
*FIELD* TI
*614589 TETRATRICOPEPTIDE REPEAT DOMAIN-CONTAINING PROTEIN 37; TTC37
;;KIAA0372
*FIELD* TX
read more
CLONING
By sequencing clones obtained from a size-fractionated human brain cDNA
library, Nagase et al. (1997) cloned TTC37, which they designated
KIAA0372. The deduced protein contains 1,564 amino acids. RT-PCR
analysis detected high expression in placenta and low expression in
kidney and ovary. Little to no expression was detected in all other
tissues examined.
Fabre et al. (2011) assessed quantitative expression of TTC37 in a panel
of 48 different tissues and found that TTC37 is widely expressed, with
the highest levels observed in vascular tissues, lymph node, pituitary,
lung, and intestine. They found no expression in liver.
MAPPING
By radiation hybrid analysis, Nagase et al. (1997) mapped the TTC37 gene
to chromosome 5.
Amberger (2012) mapped the TTC37 gene to chromosome 5q15 based on an
alignment of the TTC37 sequence (GenBank GENBANK AB002370) with the
genomic sequence (GRCh37).
MOLECULAR GENETICS
In 12 children from 11 unrelated families with trichohepatoenteric
syndrome mapping to chromosome 5q14.3-q21.2 (THES1; 222470), Hartley et
al. (2010) identified homozygosity or compound heterozygosity for 9
different mutations in the candidate gene TTC37 (see, e.g.,
614589.0001-614589.0005). Preliminary studies in 5 patients of
enterocyte brush-border ion transporter proteins, including NHE2
(SLC9A2; 600530), NHE3 (SLC9A3; 182307), NIS (SLC5A5; 601843), AQP7
(602974), and H/K ATPase (see ATP4A, 137216), demonstrated reduced
expression or mislocalization compared to controls. Hartley et al.
(2010) suggested that the multisystem effect of TTC37 mutations might be
due to abnormal stability and/or intracellular localization of TTC37
target proteins.
Fabre et al. (2011) analyzed the TTC37 gene in 12 THES patients from 11
families and identified homozygosity or compound heterozygosity for 11
different mutations in 9 of the patients (see, e.g.,
614589.0006-614589.0008).
*FIELD* AV
.0001
TRICHOHEPATOENTERIC SYNDROME 1
TTC37, TRP936TER
In 4 children with trichohepatoenteric syndrome (THES1; 222470),
including 2 sisters from an Indian family and 2 boys from 2 unrelated
consanguineous Pakistani families, Hartley et al. (2010) identified
homozygosity for a 2808G-A transition in exon 28 of the TTC37 gene,
resulting in a trp936-to-ter (W936X) substitution. SNP haplotypes in the
affected individuals were identical over a 974-kb region containing
TTC37, from SNP dbSNP rs255375 to SNP dbSNP rs34897, consistent with a
founder mutation. The mutation segregated with disease in each family
and was not found in at least 350 ethnically matched South Asian and
Caucasian control chromosomes. All 4 children had intrauterine growth
retardation, villous atrophy on jejunal biopsies, and trichorrhexis
nodosa. The Indian sisters, who both exhibited thrombocytosis and large
platelets, died at 6 months of age; 1 sib also had a ventricular septal
defect. The Pakistani boys had no platelet abnormalities or cardiac
defects; 1 died at 8 years of age, whereas the other was alive at 1 year
of age. Analysis of enterocyte brush-border ion transporter proteins in
1 of the patients demonstrated that apical expression of AQP7 (602974)
was absent, suggesting that TTC37 may regulate expression of AQP7.
.0002
TRICHOHEPATOENTERIC SYNDROME 1
TTC37, IVS28, G-A, -2
In an 11-year-old Pakistani girl and an unrelated 3.5-year-old Pakistani
boy with trichohepatoenteric syndrome-1 (222470), both from
consanguineous families, Hartley et al. (2010) identified homozygosity
for a G-A transition at -2 in intron 28 (2779-2G-A) in the TTC37 gene,
predicted to cause skipping of exon 29 and premature termination. The
mutation segregated with disease in both families and was not found in
at least 350 ethnically matched South Asian and Caucasian control
chromosomes. Both children had intrauterine growth retardation,
characteristic facial dysmorphology, villous atrophy on jejunal
biopsies, trichorrhexis nodosa, and low immunoglobulins, and both
exhibited developmental delay. In addition, the girl had mild aortic
insufficiency and the boy had peripheral pulmonary stenosis. Analysis of
enterocyte brush-border ion transporter proteins in the 2 patients
demonstrated that apical expression of H/K ATPase (see ATP4A, 137216)
was reduced and that of AQP7 (602974) was absent, and there was
mislocalization of NHE2 (SLC9A2; 600530), NHE3 (SLC9A3; 182307), and NIS
(SLC5A5; 601843) compared to controls, suggesting that the multisystem
effect of TTC37 mutations might be due to abnormal stability and/or
intracellular localization of TTC37 target proteins.
.0003
TRICHOHEPATOENTERIC SYNDROME 1
TTC37, IVS17, 1-BP DEL, G, +1
In a 2.5-year-old girl from a consanguineous Kurdish family with
trichohepatoenteric syndrome-1 (222470), Hartley et al. (2010)
identified homozygosity for a 1-bp deletion in intron 17 (1632+1delG) of
the TTC37 gene, producing a frameshift predicted to result in a
premature termination codon. The mutation segregated with disease in the
family and was not found in at least 350 ethnically matched South Asian
and Caucasian control chromosomes. Analysis of enterocyte brush-border
ion transporter proteins in the patient demonstrated that apical
expression of H/K ATPase (see ATP4A, 137216) was reduced and that of
AQP7 (602974) was absent.
.0004
TRICHOHEPATOENTERIC SYNDROME 1
TTC37, GLN147TER
In a 13-year-old Italian girl with trichohepatoenteric syndrome-1
(222470), Hartley et al. (2010) identified compound heterozygosity for a
439C-T transition in exon 8 of the TTC37 gene, resulting in a
gln147-to-ter (Q147X) substitution, and a 2251C-T transition in exon 21,
resulting in a gln751-to-ter (Q751X; 614589.0005) substitution. The
mutations segregated with disease in the family and were not found in at
least 350 ethnically matched South Asian and Caucasian control
chromosomes. Features in this patient included intrauterine growth
retardation, characteristic facial dysmorphology, villous atrophy on
jejunal biopsy, trichorrhexis nodosa, diffuse hypopigmentation of the
skin, low immunoglobulins, aortic insufficiency, and developmental
delay.
.0005
TRICHOHEPATOENTERIC SYNDROME 1
TTC37, GLN751TER
See 614589.0004 and Hartley et al. (2010).
.0006
TRICHOHEPATOENTERIC SYNDROME 1
TTC37, IVS23, G-C, +1
In a North African patient with trichohepatoenteric syndrome (222470),
Fabre et al. (2011) identified homozygosity for a G-C transversion in
intron 23 (2515+1G-C) of the TTC37 gene. Direct sequencing of RNA
transcripts from lymphoblastoid cells revealed that the mutation caused
a frameshift and creation of a premature termination codon. The mutation
was found in heterozygosity in the unaffected parents.
.0007
TRICHOHEPATOENTERIC SYNDROME 1
TTC37, IVS24, 5-BP DEL, -7
In a French patient with trichohepatoenteric syndrome-1 (222470), Fabre
et al. (2011) identified compound heterozygosity for a 5-bp deletion in
IVS24 (2577-7_-3delTTTTT) of the TTC37 gene, and a G-C transversion in
IVS42 (4620+1G-C; 614589.0008). Direct sequencing of RNA transcripts
from lymphoblastoid cells revealed that the 2577-7_-3delTTTT mutation
caused skipping of exon 25, resulting in the deletion of 19 in-frame
amino acids, whereas the 4620+1G-C mutation caused cryptic splice
activation in exon 42, resulting in alternative splicing and the
replacement of the 41 terminal amino acids by 61 others.
.0008
TRICHOHEPATOENTERIC SYNDROME 1
TTC37, IVS42, G-C, +1
See 614589.0007 and Fabre et al. (2011).
*FIELD* RF
1. Amberger, J. S.: Personal Communication. Baltimore, Md. 4/24/2012.
2. Fabre, A.; Martinez-Vinson, C.; Roquelaure, B.; Missirian, C.;
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*FIELD* CN
Marla J. F. O'Neill - updated: 4/27/2012
*FIELD* CD
Joanna S. Amberger: 4/24/2012
*FIELD* ED
carol: 09/11/2013
mgross: 2/26/2013
carol: 4/27/2012
mgross: 4/24/2012
joanna: 4/24/2012