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          Institute: MPI für molekulare Genetik     Collection: Research Group Development and Disease     Display Documents



  history
ID: 174918.0, MPI für molekulare Genetik / Research Group Development and Disease
Mutations in bone morphogenetic protein receptor 1B cause brachydactyly type A2
Authors:Lehmann, Katarina; Seemann, Petra; Stricker, Sigmar; Sammar, Marai; Meyer, Birgit; Suering, Katrin; Majewski, Frank; Tinschert, Sigrid; Grzeschik, Karl-Heinz H.; Mueller, Dietmar; Knaus, Petra; Nurnberg, Peter; Mundlos, Stefan
Language:English
Date of Publication (YYYY-MM-DD):2003-10-14
Title of Journal:Proceedings of the National Academy of Sciences of the United States of America
Journal Abbrev.:Proc. Natl. Acad. Sci. U. S. A.
Volume:100
Issue / Number:21
Start Page:12277
End Page:12282
Copyright:Copyright © 2003 by the National Academy of Sciences
Review Status:not specified
Audience:Experts Only
Abstract / Description:Brachydactyly (BD) type A2 is an autosomal dominant hand malformation characterized by shortening and lateral deviation of the index fingers and, to a variable degree, shortening and deviation of the first and second toes. We performed linkage analysis in two unrelated German families and mapped a locus for BD type A2 to 4q21-q25. This interval includes the gene bone morphogenetic protein receptor 1B (BMPR1B), a type I transmembrane serinethreonine kinase. In one family, we identified a T599 A mutation changing an isoleucine into a lysine residue (I200K) within the glycine/serine (GS) domain of BMPR1B, a region involved in phosphorylation of the receptor. In the other family we identified a C1456 T mutation leading to an arginine-to-tryptophan amino acid change (R486W) in a highly conserved region C-terminal of the BMPR1B kinase domain. An in vitro kinase assay showed that the I200K mutation is kinase-deficient, whereas the R486W mutation has normal kinase activity, indicating a different pathogenic mechanism. Functional analyses with a micromass culture system revealed a strong inhibition of chondrogenesis by both mutant receptors. Overexpression of mutant chBmpR1b in vivo in chick embryos by using a retroviral system resulted either in a BD phenotype with shortening and/or missing phalanges similar to the human phenotype or in severe hypoplasia of the entire limb. These findings imply that both mutations identified in human BMPR1B affect cartilage formation in a dominant-negative manner.
Comment of the Author/Creator:published online before print October 1 2003
External Publication Status:published
Document Type:Article
Version Comment:Automatic journal name synchronization
Communicated by:Stefan Mundlos
Affiliations:MPI für molekulare Genetik
External Affiliations:Humboldt Univ, Charite, Inst Med Genet, D-13353 Berlin, Germany.; Max Planck Inst Mol Genet, D-14195 Berlin, Germany.; Univ Wuerzburg, Inst Physiol Chem 2, D-97074 Wuerzburg, Germany.; Max Delbrueck Ctr Mol Med, Genkartierungszentrum, D-13125 Berlin, Germany.; Univ Klin Duesseldorf, Inst Human Genet, D-40225 Duesseldorf, Germany.; Univ Klin Marburg, Inst Allgemeine Human Genet, D-35037 Marburg, Germany.; Klinikum Chemnitz, Inst Med Genet, D-09116 Chemnitz, Germany.
Identifiers:ISI:000186024300063 [ID No:1]
ISSN:0027-8424 [ID No:2]
DOI:10.1073/pnas.2133476100 [ID No:3]
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