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Article: A mutation in Ihh that causes digit abnormalities alters its signalling capacity and range

TitleA mutation in Ihh that causes digit abnormalities alters its signalling capacity and range
Authors
Issue Date2009
PublisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/nature
Citation
Nature, 2009, v. 458 n. 7242, p. 1196-1200 How to Cite?
AbstractBrachydactyly type A1 (BDA1) was the first recorded disorder of the autosomal dominant Mendelian trait in humans, characterized by shortened or absent middle phalanges in digits. It is associated with heterozygous missense mutations in indian hedgehog (IHH). Hedgehog proteins are important morphogens for a wide range of developmental processes. The capacity and range of signalling is thought to be regulated by its interaction with the receptor PTCH1 and antagonist HIP1. Here we show that a BDA1 mutation (E95K) in Ihh impairs the interaction of IHH with PTCH1 and HIP1. This is consistent with a recent paper showing that BDA1 mutations cluster in a calcium-binding site essential for the interaction with its receptor and cell-surface partners. Furthermore, we show that in a mouse model that recapitulates the E95K mutation, there is a change in the potency and range of signalling. The mice have digit abnormalities consistent with the human disorder. © 2009 Macmillan Publishers Limited.
Persistent Identifierhttp://hdl.handle.net/10722/147604
ISSN
2015 Impact Factor: 38.138
2015 SCImago Journal Rankings: 21.936
ISI Accession Number ID
Funding AgencyGrant Number
Research Grants CouncilN_HKU705/02
HKU2/02C
University Grants Council of Hong KongAoE/M-04/04
National Key Scientific Program2007CB947300
Funding Information:

This work was supported by grants from the Research Grants Council and University Grants Council of Hong Kong (N_HKU705/02, HKU2/02C and AoE/M-04/04), and The National Key Scientific Program (2007CB947300). We thank P. Tam for suggestions and comments, P. Beachy and D. Leahy for sharing unpublished data, and K. Leung for blastocyst injections.

References
Grants

 

DC FieldValueLanguage
dc.contributor.authorGao, Ben_US
dc.contributor.authorHu, Jen_US
dc.contributor.authorStricker, Sen_US
dc.contributor.authorCheung, Men_US
dc.contributor.authorMa, Gen_US
dc.contributor.authorLaw, KFen_US
dc.contributor.authorWitte, Fen_US
dc.contributor.authorBriscoe, Jen_US
dc.contributor.authorMundlos, Sen_US
dc.contributor.authorHe, Len_US
dc.contributor.authorCheah, KSEen_US
dc.contributor.authorChan, Den_US
dc.date.accessioned2012-05-29T06:04:55Z-
dc.date.available2012-05-29T06:04:55Z-
dc.date.issued2009en_US
dc.identifier.citationNature, 2009, v. 458 n. 7242, p. 1196-1200en_US
dc.identifier.issn0028-0836en_US
dc.identifier.urihttp://hdl.handle.net/10722/147604-
dc.description.abstractBrachydactyly type A1 (BDA1) was the first recorded disorder of the autosomal dominant Mendelian trait in humans, characterized by shortened or absent middle phalanges in digits. It is associated with heterozygous missense mutations in indian hedgehog (IHH). Hedgehog proteins are important morphogens for a wide range of developmental processes. The capacity and range of signalling is thought to be regulated by its interaction with the receptor PTCH1 and antagonist HIP1. Here we show that a BDA1 mutation (E95K) in Ihh impairs the interaction of IHH with PTCH1 and HIP1. This is consistent with a recent paper showing that BDA1 mutations cluster in a calcium-binding site essential for the interaction with its receptor and cell-surface partners. Furthermore, we show that in a mouse model that recapitulates the E95K mutation, there is a change in the potency and range of signalling. The mice have digit abnormalities consistent with the human disorder. © 2009 Macmillan Publishers Limited.en_US
dc.languageengen_US
dc.publisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/natureen_US
dc.relation.ispartofNatureen_US
dc.subject.meshAnimalsen_US
dc.subject.meshChickensen_US
dc.subject.meshDna-Binding Proteins - Genetics - Metabolismen_US
dc.subject.meshDisease Models, Animalen_US
dc.subject.meshFemaleen_US
dc.subject.meshHedgehog Proteins - Genetics - Metabolismen_US
dc.subject.meshHumansen_US
dc.subject.meshLimb Deformities, Congenital - Genetics - Metabolismen_US
dc.subject.meshMaleen_US
dc.subject.meshMiceen_US
dc.subject.meshMice, Inbred C57blen_US
dc.subject.meshMice, Mutant Strainsen_US
dc.subject.meshMutation - Geneticsen_US
dc.subject.meshProtein Bindingen_US
dc.subject.meshReceptors, Cell Surface - Genetics - Metabolismen_US
dc.subject.meshSignal Transductionen_US
dc.titleA mutation in Ihh that causes digit abnormalities alters its signalling capacity and rangeen_US
dc.typeArticleen_US
dc.identifier.emailCheung, M:mcheung9@hkucc.hku.hken_US
dc.identifier.emailCheah, KSE:hrmbdkc@hku.hken_US
dc.identifier.emailChan, D:chand@hkucc.hku.hken_US
dc.identifier.authorityCheung, M=rp00245en_US
dc.identifier.authorityCheah, KSE=rp00342en_US
dc.identifier.authorityChan, D=rp00540en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1038/nature07862en_US
dc.identifier.pmid19252479-
dc.identifier.scopuseid_2-s2.0-67349243876en_US
dc.identifier.hkuros155478-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-67349243876&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume458en_US
dc.identifier.issue7242en_US
dc.identifier.spage1196en_US
dc.identifier.epage1200en_US
dc.identifier.eissn1476-4687-
dc.identifier.isiWOS:000265754600052-
dc.publisher.placeUnited Kingdomen_US
dc.identifier.f10001165683-
dc.relation.projectDevelopmental genomics and skeletal research-
dc.identifier.scopusauthoridGao, B=24481275100en_US
dc.identifier.scopusauthoridHu, J=25121188100en_US
dc.identifier.scopusauthoridStricker, S=7005436014en_US
dc.identifier.scopusauthoridCheung, M=7201897461en_US
dc.identifier.scopusauthoridMa, G=54915525100en_US
dc.identifier.scopusauthoridLaw, KF=24776036500en_US
dc.identifier.scopusauthoridWitte, F=24436519800en_US
dc.identifier.scopusauthoridBriscoe, J=7005150612en_US
dc.identifier.scopusauthoridMundlos, S=7005248176en_US
dc.identifier.scopusauthoridHe, L=36080215400en_US
dc.identifier.scopusauthoridCheah, KSE=35387746200en_US
dc.identifier.scopusauthoridChan, D=7402216545en_US
dc.identifier.citeulike4118381-

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