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Article: Indian hedgehog mutations causing brachydactyly type A1 impair Hedgehog signal transduction at multiple levels
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TitleIndian hedgehog mutations causing brachydactyly type A1 impair Hedgehog signal transduction at multiple levels
 
AuthorsMa, G6 3
Yu, J8
Xiao, Y6 3
Chan, D2 1
Gao, B3
Hu, J2 3
He, Y8
Guo, S6 3
Zhou, J6 3
Zhang, L6 3
Gao, L6 3
Zhang, W8
Kang, Y8
Cheah, KSE2 1
Feng, G7
Guo, X3
Wang, Y3 4
Zhou, CZ8
He, L6 5 3
 
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
 
CitationCell Research, 2011, v. 21 n. 9, p. 1343-1357 [How to Cite?]
DOI: http://dx.doi.org/10.1038/cr.2011.76
 
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.
 
ISSN1001-0602
2013 Impact Factor: 11.981
 
DOIhttp://dx.doi.org/10.1038/cr.2011.76
 
PubMed Central IDPMC3193471
 
ISI Accession Number IDWOS:000294492500009
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).

 
ReferencesReferences in Scopus
 
DC FieldValue
dc.contributor.authorMa, G
 
dc.contributor.authorYu, J
 
dc.contributor.authorXiao, Y
 
dc.contributor.authorChan, D
 
dc.contributor.authorGao, B
 
dc.contributor.authorHu, J
 
dc.contributor.authorHe, Y
 
dc.contributor.authorGuo, S
 
dc.contributor.authorZhou, J
 
dc.contributor.authorZhang, L
 
dc.contributor.authorGao, L
 
dc.contributor.authorZhang, W
 
dc.contributor.authorKang, Y
 
dc.contributor.authorCheah, KSE
 
dc.contributor.authorFeng, G
 
dc.contributor.authorGuo, X
 
dc.contributor.authorWang, Y
 
dc.contributor.authorZhou, CZ
 
dc.contributor.authorHe, L
 
dc.date.accessioned2011-09-23T05:43:10Z
 
dc.date.available2011-09-23T05:43:10Z
 
dc.date.issued2011
 
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.
 
dc.description.natureLink_to_subscribed_fulltext
 
dc.identifier.citationCell Research, 2011, v. 21 n. 9, p. 1343-1357 [How to Cite?]
DOI: http://dx.doi.org/10.1038/cr.2011.76
 
dc.identifier.doihttp://dx.doi.org/10.1038/cr.2011.76
 
dc.identifier.epage1357
 
dc.identifier.hkuros192843
 
dc.identifier.isiWOS:000294492500009
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).

 
dc.identifier.issn1001-0602
2013 Impact Factor: 11.981
 
dc.identifier.issue9
 
dc.identifier.openurl
 
dc.identifier.pmcidPMC3193471
 
dc.identifier.pmid21537345
 
dc.identifier.scopuseid_2-s2.0-80052446523
 
dc.identifier.spage1343
 
dc.identifier.urihttp://hdl.handle.net/10722/138961
 
dc.identifier.volume21
 
dc.languageeng
 
dc.publisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/cr/marketing/index.html
 
dc.publisher.placeUnited Kingdom
 
dc.relation.ispartofCell Research
 
dc.relation.referencesReferences in Scopus
 
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.subjectBDA1
 
dc.subjectcrystal structure
 
dc.subjectdegradation
 
dc.subjectdiffusion
 
dc.subjectheparin
 
dc.subjectIndian hedgehog
 
dc.titleIndian hedgehog mutations causing brachydactyly type A1 impair Hedgehog signal transduction at multiple levels
 
dc.typeArticle
 
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Author Affiliations
  1. The University of Hong Kong Li Ka Shing Faculty of Medicine
  2. The University of Hong Kong
  3. Shanghai Jiaotong University
  4. Ningxia University
  5. Fudan University Shanghai Medical College
  6. Shanghai Institute for Biological Sciences Chinese Academy of Sciences
  7. Shanghai Mental Health Center
  8. Hefei National Laboratory for Physical Sciences at Microscale