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Article: Differential contributions of rare and common, coding and noncoding ret mutations to multifactorial hirschsprung disease liability

TitleDifferential contributions of rare and common, coding and noncoding ret mutations to multifactorial hirschsprung disease liability
Authors
Issue Date2010
PublisherCell Press. The Journal's web site is located at http://www.cell.com/AJHG/
Citation
American Journal Of Human Genetics, 2010, v. 87 n. 1, p. 60-74 How to Cite?
AbstractThe major gene for Hirschsprung disease (HSCR) encodes the receptor tyrosine kinase RET. In a study of 690 European- and 192 Chinese-descent probands and their parents or controls, we demonstrate the ubiquity of a >4-fold susceptibility from a C→T allele (rs2435357: p = 3.9 × 10-43 in European ancestry; p = 1.1 × 10-21 in Chinese samples) that probably arose once within the intronic RET enhancer MCS+9.7. With in vitro assays, we now show that the T variant disrupts a SOX10 binding site within MCS+9.7 that compromises RET transactivation. The T allele, with a control frequency of 20%-30%/47% and case frequency of 54%-62%/88% in European/Chinese-ancestry individuals, is involved in all forms of HSCR. It is marginally associated with proband gender (p = 0.13) and significantly so with length of aganglionosis (p = 7.6 × 10-5) and familiality (p = 6.2 × 10-4). The enhancer variant is more frequent in the common forms of male, short-segment, and simplex families whereas multiple, rare, coding mutations are the norm in the less common and more severe forms of female, long-segment, and multiplex families. The T variant also increases penetrance in patients with rare RET coding mutations. Thus, both rare and common mutations, individually and together, make contributions to the risk of HSCR. The distribution of RET variants in diverse HSCR patients suggests a "cellular-recessive" genetic model where both RET alleles' function is compromised. The RET allelic series, and its genotype-phenotype correlations, shows that success in variant identification in complex disorders may strongly depend on which patients are studied. © 2010 The American Society of Human Genetics. All rights reserved.
Persistent Identifierhttp://hdl.handle.net/10722/125450
ISSN
2015 Impact Factor: 10.794
2015 SCImago Journal Rankings: 8.769
PubMed Central ID
ISI Accession Number ID
Funding AgencyGrant Number
(USA) National Institutes of HealthHD28088
GM71648
"Holes for Hirschsprung"
(Italy) Italian TelethonGGP04257
European "E-Rare" program-Istituto Superiore di Sanita (Italy)PI071315
(France) ANR
FRM (Fondation pour la Recherche Medicale)
Hong Kong Research Grant CouncilHKU 765407
(Netherlands) NWO901-04-225
Bernoulle Foundation
Ubbo Emmius Foundation
Fondo de Investigacion Sanitaria, SpainPI070080
Consejeria de Educacion Ciencia Y Empresa de la Junta de AndaluciaCTS2590
Funding Information:

We wish to thank the numerous patients, their families, and the referring physicians across the world that have participated in studies of Hirschsprung disease in our laboratories over the past 20 years, and the numerous laboratory members who have contributed to discussion of these results. This study is a contribution from The International Hirschsprung Disease Consortium. Grant support is as follows: (USA) National Institutes of Health, HD28088 to A.C. and GM71648 to A.S.M.; and the "Holes for Hirschsprung" fundraiser to A.C.; (Italy) Italian Telethon (GGP04257) and European "E-Rare" program-Istituto Superiore di Sanita (Italy) to I.C.; (France) ANR (Eranet and Maladies Rares Grants) and FRM (Fondation pour la Recherche Medicale) to S.L.; (Hong Kong) HKU 765407 from the Hong Kong Research Grant Council to M.G.-B. and P.K.H.T.; (Netherlands) NWO (no. 901-04-225) Bernoulle Foundation and Ubbo Emmius Foundation to R.M.W.H.; and (Spain) Fondo de Investigacion Sanitaria, Spain (PI070080), European E:Rare program (PI071315), and Consejeria de Educacion Ciencia Y Empresa de la Junta de Andalucia (CTS2590) to S.B. Author contributions are as follows. (USA) A.C. designed the study and ascertained families; E.S.E. and K.W. performed all genotyping; L.H. and E.S.E. performed DNA sequence analysis; E.A.G. and A.S.M. designed and performed the functional enhancer biological analyses; C.K., E.S.E., and A.C. conducted statistical analysis of the data; and E.S.E., A.S.M., and A.C. participated in data interpretation and writing the manuscript. We gratefully acknowledge the work of Erick Kaufmann, Jennifer (Scott) Bubb, Maura Kenton, Julie Albertus, and Courtney Nichols in family ascertainment. (Italy) F.L. and I.C. ascertained families; F.L. conducted statistical analysis of data; and F.L., P.G., and I.C. participated in data interpretation and editing the manuscript. (France) J.A., A.P., and L.d.P. performed DNA sequencing; A.-S.J. conducted statistical analyses of data; and J.A. and S.L. participated in the study design, data interpretation, and ascertainment of families. (Hong Kong) M.G.-B. and X.M. performed DNA sequencing and genotyping of the sporadic Chinese HSCR patients and control samples; M.G.-B. conducted statistical analysis of data, and together with P.K.H.T., data interpretation; and P.K.H.T. ascertained all Chinese HSCR patients. (Netherlands) G.B. performed all genotyping; R.M.W.H. participated in data interpretation and manuscript editing; and J.B.G.M.V. was involved in ascertaining families. (Spain) S.B. and G.A. ascertained Spanish HSCR families; R.M.F. performed DNA sequencing for mutation detection; and R.M.F., G.A., and S.B. participated in manuscript editing.

References

 

DC FieldValueLanguage
dc.contributor.authorEmison, ESen_HK
dc.contributor.authorGarciaBarcelo, Men_HK
dc.contributor.authorGrice, EAen_HK
dc.contributor.authorLantieri, Fen_HK
dc.contributor.authorAmiel, Jen_HK
dc.contributor.authorBurzynski, Gen_HK
dc.contributor.authorFernandez, RMen_HK
dc.contributor.authorHao, Len_HK
dc.contributor.authorKashuk, Cen_HK
dc.contributor.authorWest, Ken_HK
dc.contributor.authorMiao, Xen_HK
dc.contributor.authorTam, PKHen_HK
dc.contributor.authorGriseri, Pen_HK
dc.contributor.authorCeccherini, Ien_HK
dc.contributor.authorPelet, Aen_HK
dc.contributor.authorJannot, ASen_HK
dc.contributor.authorDe Pontual, Len_HK
dc.contributor.authorHenrionCaude, Aen_HK
dc.contributor.authorLyonnet, Sen_HK
dc.contributor.authorVerheij, JBGMen_HK
dc.contributor.authorHofstra, RMWen_HK
dc.contributor.authorAntiñolo, Gen_HK
dc.contributor.authorBorrego, Sen_HK
dc.contributor.authorMcCallion, ASen_HK
dc.contributor.authorChakravarti, Aen_HK
dc.date.accessioned2010-10-31T11:32:07Z-
dc.date.available2010-10-31T11:32:07Z-
dc.date.issued2010en_HK
dc.identifier.citationAmerican Journal Of Human Genetics, 2010, v. 87 n. 1, p. 60-74en_HK
dc.identifier.issn0002-9297en_HK
dc.identifier.urihttp://hdl.handle.net/10722/125450-
dc.description.abstractThe major gene for Hirschsprung disease (HSCR) encodes the receptor tyrosine kinase RET. In a study of 690 European- and 192 Chinese-descent probands and their parents or controls, we demonstrate the ubiquity of a >4-fold susceptibility from a C→T allele (rs2435357: p = 3.9 × 10-43 in European ancestry; p = 1.1 × 10-21 in Chinese samples) that probably arose once within the intronic RET enhancer MCS+9.7. With in vitro assays, we now show that the T variant disrupts a SOX10 binding site within MCS+9.7 that compromises RET transactivation. The T allele, with a control frequency of 20%-30%/47% and case frequency of 54%-62%/88% in European/Chinese-ancestry individuals, is involved in all forms of HSCR. It is marginally associated with proband gender (p = 0.13) and significantly so with length of aganglionosis (p = 7.6 × 10-5) and familiality (p = 6.2 × 10-4). The enhancer variant is more frequent in the common forms of male, short-segment, and simplex families whereas multiple, rare, coding mutations are the norm in the less common and more severe forms of female, long-segment, and multiplex families. The T variant also increases penetrance in patients with rare RET coding mutations. Thus, both rare and common mutations, individually and together, make contributions to the risk of HSCR. The distribution of RET variants in diverse HSCR patients suggests a "cellular-recessive" genetic model where both RET alleles' function is compromised. The RET allelic series, and its genotype-phenotype correlations, shows that success in variant identification in complex disorders may strongly depend on which patients are studied. © 2010 The American Society of Human Genetics. All rights reserved.en_HK
dc.languageengen_HK
dc.publisherCell Press. The Journal's web site is located at http://www.cell.com/AJHG/en_HK
dc.relation.ispartofAmerican Journal of Human Geneticsen_HK
dc.subject.meshAsian Continental Ancestry Group-
dc.subject.meshEuropean Continental Ancestry Group-
dc.subject.meshGenome-Wide Association Study-
dc.subject.meshHirschsprung Disease - ethnology - genetics - physiopathology-
dc.subject.meshProto-Oncogene Proteins c-ret - genetics - metabolism-
dc.titleDifferential contributions of rare and common, coding and noncoding ret mutations to multifactorial hirschsprung disease liabilityen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0002-9297&volume=87&issue=1&spage=60&epage=74&date=2010&atitle=Differential+contributions+of+rare+and+common,+coding+and+noncoding+Ret+mutations+to+multifactorial+Hirschsprung+disease+liability-
dc.identifier.emailGarciaBarcelo, M: mmgarcia@hkucc.hku.hken_HK
dc.identifier.emailTam, PKH: paultam@hkucc.hku.hken_HK
dc.identifier.authorityGarciaBarcelo, M=rp00445en_HK
dc.identifier.authorityTam, PKH=rp00060en_HK
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1016/j.ajhg.2010.06.007en_HK
dc.identifier.pmid20598273-
dc.identifier.pmcidPMC2896767-
dc.identifier.scopuseid_2-s2.0-77955081986en_HK
dc.identifier.hkuros173370en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-77955081986&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume87en_HK
dc.identifier.issue1en_HK
dc.identifier.spage60en_HK
dc.identifier.epage74en_HK
dc.identifier.eissn1537-6605-
dc.identifier.isiWOS:000280029200006-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridEmison, ES=8333201700en_HK
dc.identifier.scopusauthoridGarciaBarcelo, M=6701767303en_HK
dc.identifier.scopusauthoridGrice, EA=6507663126en_HK
dc.identifier.scopusauthoridLantieri, F=6506772531en_HK
dc.identifier.scopusauthoridAmiel, J=7102312975en_HK
dc.identifier.scopusauthoridBurzynski, G=8582419900en_HK
dc.identifier.scopusauthoridFernandez, RM=35324125700en_HK
dc.identifier.scopusauthoridHao, L=36342553400en_HK
dc.identifier.scopusauthoridKashuk, C=7801364395en_HK
dc.identifier.scopusauthoridWest, K=14020757700en_HK
dc.identifier.scopusauthoridMiao, X=7102585391en_HK
dc.identifier.scopusauthoridTam, PKH=7202539421en_HK
dc.identifier.scopusauthoridGriseri, P=6602563929en_HK
dc.identifier.scopusauthoridCeccherini, I=7004367074en_HK
dc.identifier.scopusauthoridPelet, A=7004252827en_HK
dc.identifier.scopusauthoridJannot, AS=6507981039en_HK
dc.identifier.scopusauthoridDe Pontual, L=6602706116en_HK
dc.identifier.scopusauthoridHenrionCaude, A=6602277720en_HK
dc.identifier.scopusauthoridLyonnet, S=35432935300en_HK
dc.identifier.scopusauthoridVerheij, JBGM=7003347665en_HK
dc.identifier.scopusauthoridHofstra, RMW=7006771436en_HK
dc.identifier.scopusauthoridAntiñolo, G=7003760578en_HK
dc.identifier.scopusauthoridBorrego, S=7004133244en_HK
dc.identifier.scopusauthoridMcCallion, AS=6603112386en_HK
dc.identifier.scopusauthoridChakravarti, A=35355137200en_HK

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