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Article: Indian hedgehog mutations causing brachydactyly type A1 impair Hedgehog signal transduction at multiple levels

TitleIndian hedgehog mutations causing brachydactyly type A1 impair Hedgehog signal transduction at multiple levels
Authors
KeywordsBDA1
crystal structure
degradation
diffusion
heparin
Indian hedgehog
Issue Date2011
PublisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/cr/marketing/index.html
Citation
Cell Research, 2011, v. 21 n. 9, p. 1343-1357 How to Cite?
AbstractBrachydactyly type A1 (BDA1), the first recorded Mendelian autosomal dominant disorder in humans, is characterized by a shortening or absence of the middle phalanges. Heterozygous missense mutations in the Indian Hedgehog (IHH) gene have been identified as a cause of BDA1; however, the biochemical consequences of these mutations are unclear. In this paper, we analyzed three BDA1 mutations (E95K, D100E, and E131K) in the N-terminal fragment of Indian Hedgehog (IhhN). Structural analysis showed that the E95K mutation changes a negatively charged area to a positively charged area in a calcium-binding groove, and that the D100E mutation changes the local tertiary structure. Furthermore, we showed that the E95K and D100E mutations led to a temperature-sensitive and calcium-dependent instability of IhhN, which might contribute to an enhanced intracellular degradation of the mutant proteins via the lysosome. Notably, all three mutations affected Hh binding to the receptor Patched1 (PTC1), reducing its capacity to induce cellular differentiation. We propose that these are common features of the mutations that cause BDA1, affecting the Hh tertiary structure, intracellular fate, binding to the receptor/partners, and binding to extracellular components. The combination of these features alters signaling capacity and range, but the impact is likely to be variable and mutation-dependent. The potential variation in the signaling range is characterized by an enhanced interaction with heparan sulfate for IHH with the E95K mutation, but not the E131K mutation. Taken together, our results suggest that these IHH mutations affect Hh signaling at multiple levels, causing abnormal bone development and abnormal digit formation. © 2011 IBCB, SIBS, CAS All rights reserved.
Persistent Identifierhttp://hdl.handle.net/10722/138961
ISSN
2015 Impact Factor: 14.812
2015 SCImago Journal Rankings: 4.805
PubMed Central ID
ISI Accession Number ID
Funding AgencyGrant Number
National Natural Science Foundation of China30800613
973 Program2010CB529600
2007CB947300
863 Program2009AA022701
Shanghai Municipal Commission09DJ1400601
Natural Science Foundation of Shanghai, China08ZR1411000
National Key Project for the Investigation of New Drugs2008ZX09312-003
Shanghai Leading Academic Discipline ProjectB205
General Research Fund of Hong KongHKU760608M
"Pujiang Talent" Project08PJ1407200
Funding Information:

This work was supported by the National Natural Science Foundation of China (30800613), the 973 Program (2010CB529600, 2007CB947300), the 863 Program (2009AA022701), the Shanghai Municipal Commission of Science and Technology Program (09DJ1400601), the Natural Science Foundation of Shanghai, China (Grant No. 08ZR1411000), the National Key Project for the Investigation of New Drugs (2008ZX09312-003), the Shanghai Leading Academic Discipline Project (B205), and the General Research Fund of Hong Kong (HKU760608M). The coauthor, Xizhi Guo, was supported by the "Pujiang Talent" Project (08PJ1407200).

References

 

DC FieldValueLanguage
dc.contributor.authorMa, Gen_HK
dc.contributor.authorYu, Jen_HK
dc.contributor.authorXiao, Yen_HK
dc.contributor.authorChan, Den_HK
dc.contributor.authorGao, Ben_HK
dc.contributor.authorHu, Jen_HK
dc.contributor.authorHe, Yen_HK
dc.contributor.authorGuo, Sen_HK
dc.contributor.authorZhou, Jen_HK
dc.contributor.authorZhang, Len_HK
dc.contributor.authorGao, Len_HK
dc.contributor.authorZhang, Wen_HK
dc.contributor.authorKang, Yen_HK
dc.contributor.authorCheah, KSEen_HK
dc.contributor.authorFeng, Gen_HK
dc.contributor.authorGuo, Xen_HK
dc.contributor.authorWang, Yen_HK
dc.contributor.authorZhou, CZen_HK
dc.contributor.authorHe, Len_HK
dc.date.accessioned2011-09-23T05:43:10Z-
dc.date.available2011-09-23T05:43:10Z-
dc.date.issued2011en_HK
dc.identifier.citationCell Research, 2011, v. 21 n. 9, p. 1343-1357en_HK
dc.identifier.issn1001-0602en_HK
dc.identifier.urihttp://hdl.handle.net/10722/138961-
dc.description.abstractBrachydactyly type A1 (BDA1), the first recorded Mendelian autosomal dominant disorder in humans, is characterized by a shortening or absence of the middle phalanges. Heterozygous missense mutations in the Indian Hedgehog (IHH) gene have been identified as a cause of BDA1; however, the biochemical consequences of these mutations are unclear. In this paper, we analyzed three BDA1 mutations (E95K, D100E, and E131K) in the N-terminal fragment of Indian Hedgehog (IhhN). Structural analysis showed that the E95K mutation changes a negatively charged area to a positively charged area in a calcium-binding groove, and that the D100E mutation changes the local tertiary structure. Furthermore, we showed that the E95K and D100E mutations led to a temperature-sensitive and calcium-dependent instability of IhhN, which might contribute to an enhanced intracellular degradation of the mutant proteins via the lysosome. Notably, all three mutations affected Hh binding to the receptor Patched1 (PTC1), reducing its capacity to induce cellular differentiation. We propose that these are common features of the mutations that cause BDA1, affecting the Hh tertiary structure, intracellular fate, binding to the receptor/partners, and binding to extracellular components. The combination of these features alters signaling capacity and range, but the impact is likely to be variable and mutation-dependent. The potential variation in the signaling range is characterized by an enhanced interaction with heparan sulfate for IHH with the E95K mutation, but not the E131K mutation. Taken together, our results suggest that these IHH mutations affect Hh signaling at multiple levels, causing abnormal bone development and abnormal digit formation. © 2011 IBCB, SIBS, CAS All rights reserved.en_HK
dc.languageengen_US
dc.publisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/cr/marketing/index.htmlen_HK
dc.relation.ispartofCell Researchen_HK
dc.subjectBDA1en_HK
dc.subjectcrystal structureen_HK
dc.subjectdegradationen_HK
dc.subjectdiffusionen_HK
dc.subjectheparinen_HK
dc.subjectIndian hedgehogen_HK
dc.subject.meshBrachydactyly - genetics - metabolism-
dc.subject.meshHedgehog Proteins - chemistry - genetics - metabolism-
dc.subject.meshSignal Transduction-
dc.subject.meshCrystal structure-
dc.subject.meshIndian hedgehog-
dc.titleIndian hedgehog mutations causing brachydactyly type A1 impair Hedgehog signal transduction at multiple levelsen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=1001-0602&volume=&spage=&epage=&date=2011&atitle=Indian+hedgehog+mutations+causing+brachydactyly+type+A1+impair+Hedgehog+signal+transduction+at+multiple+levelsen_US
dc.identifier.emailChan, D:chand@hkucc.hku.hken_HK
dc.identifier.emailCheah, KSE:hrmbdkc@hku.hken_HK
dc.identifier.authorityChan, D=rp00540en_HK
dc.identifier.authorityCheah, KSE=rp00342en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1038/cr.2011.76en_HK
dc.identifier.pmid21537345-
dc.identifier.pmcidPMC3193471-
dc.identifier.scopuseid_2-s2.0-80052446523en_HK
dc.identifier.hkuros192843en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-80052446523&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume21en_HK
dc.identifier.issue9en_HK
dc.identifier.spage1343en_HK
dc.identifier.epage1357en_HK
dc.identifier.isiWOS:000294492500009-
dc.publisher.placeUnited Kingdomen_HK
dc.identifier.scopusauthoridMa, G=54915525100en_HK
dc.identifier.scopusauthoridYu, J=21744323000en_HK
dc.identifier.scopusauthoridXiao, Y=35314160900en_HK
dc.identifier.scopusauthoridChan, D=7402216545en_HK
dc.identifier.scopusauthoridGao, B=24481275100en_HK
dc.identifier.scopusauthoridHu, J=25121188100en_HK
dc.identifier.scopusauthoridHe, Y=50961301600en_HK
dc.identifier.scopusauthoridGuo, S=7403650670en_HK
dc.identifier.scopusauthoridZhou, J=7405551581en_HK
dc.identifier.scopusauthoridZhang, L=8694387500en_HK
dc.identifier.scopusauthoridGao, L=15756791100en_HK
dc.identifier.scopusauthoridZhang, W=50961923800en_HK
dc.identifier.scopusauthoridKang, Y=39661121500en_HK
dc.identifier.scopusauthoridCheah, KSE=35387746200en_HK
dc.identifier.scopusauthoridFeng, G=7401641914en_HK
dc.identifier.scopusauthoridGuo, X=8215748800en_HK
dc.identifier.scopusauthoridWang, Y=26022145700en_HK
dc.identifier.scopusauthoridZhou, CZ=35325964400en_HK
dc.identifier.scopusauthoridHe, L=36080215400en_HK

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