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  Mutations in bone morphogenetic protein receptor 1B cause brachydactyly type A2

Lehmann, K., Seemann, P., Stricker, S., Sammar, M., Meyer, B., Suering, K., et al. (2003). Mutations in bone morphogenetic protein receptor 1B cause brachydactyly type A2. Proceedings of the National Academy of Sciences of the United States of America, 100(21), 12277-12282. doi:10.1073/pnas.2133476100.

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Genre: Zeitschriftenartikel
Alternativer Titel : Proc. Natl. Acad. Sci. U. S. A.

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 Urheber:
Lehmann, Katarina, Autor
Seemann, Petra1, Autor           
Stricker, Sigmar1, Autor           
Sammar, Marai, Autor
Meyer, Birgit, Autor
Suering, Katrin2, Autor
Majewski, Frank, Autor
Tinschert, Sigrid1, Autor           
Grzeschik, Karl-Heinz H., Autor
Mueller, Dietmar, Autor
Knaus, Petra, Autor
Nurnberg, Peter, Autor
Mundlos, Stefan1, Autor           
Affiliations:
1Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433557              
2Max Planck Society, ou_persistent13              

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 Zusammenfassung: 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.

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Sprache(n): eng - English
 Datum: 2003-10-14
 Publikationsstatus: Erschienen
 Seiten: -
 Ort, Verlag, Ausgabe: -
 Inhaltsverzeichnis: -
 Art der Begutachtung: -
 Identifikatoren: eDoc: 174918
ISI: 000186024300063
DOI: 10.1073/pnas.2133476100
 Art des Abschluß: -

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Titel: Proceedings of the National Academy of Sciences of the United States of America
  Alternativer Titel : Proc. Natl. Acad. Sci. U. S. A.
Genre der Quelle: Zeitschrift
 Urheber:
Affiliations:
Ort, Verlag, Ausgabe: -
Seiten: - Band / Heft: 100 (21) Artikelnummer: - Start- / Endseite: 12277 - 12282 Identifikator: ISSN: 0027-8424