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

ID: 313090.0, MPI für molekulare Genetik / Research Group Development and Disease
A novel R486Q mutation in BMPR1B resulting in either a brachydactyly type C/symphalangism-like phenotype or brachydactyly type A2
Authors:Lehmann, Katarina; Seemann, Petra; Boergermann, Jan; Morin, Gilles; Reif, Silke; Knaus, Petra; Mundlos, Stefan
Date of Publication (YYYY-MM-DD):2006-12
Title of Journal:European Journal of Human Genetics
Journal Abbrev.:Eur J Human Genet
Issue / Number:12
Start Page:1248
End Page:1254
Copyright:© 2007 European Society of Human Genetics
Review Status:not specified
Audience:Experts Only
Abstract / Description:Heterozygous missense mutations in the serine-threonine kinase receptor BMPR1B result typically in brachydactyly type A2 (BDA2), whereas mutations in the corresponding ligand GDF5 cause brachydactyly type C (BDC). Mutations in the GDF inhibitor Noggin (NOG) or activating mutations in GDF5 cause proximal symphalangism (SYM1). Here, we describe a novel mutation in BMPR1B (R486Q) that is associated with either BDA2 or a BDC/SYM1-like phenotype. Functional investigations of the R486Q mutation were performed and compared with the previously reported BDA2-causing mutation R486W and WT BMPR1B. Overexpression of the mutant receptors in chicken micromass cultures resulted in a strong inhibition of chondrogenesis with the R486Q mutant, showing a stronger effect than the R486W mutant. To investigate the consequences of the BMPR1B mutations on the intracellular signal transduction, we used stably transfected C2C12 cells and measured the activity of SMAD-dependent and SMAD-independent pathways. SMAD activation after stimulation with GDF5 was suppressed in both mutants. Alkaline phosphatase induction showed an almost complete loss of activation by both mutants. Our data extend the previously known mutational and phenotypic spectrum associated with mutations in BMPR1B. Disturbances of NOG-GDF5-BMPR1B signaling cascade can result in similar clinical manifestations depending on the quantitative effect and mode of action of the specific mutations within the same functional pathway.
Free Keywords:bone morphogenetic protein receptors; growth differentiation factor 5; noggin; brachydactyly; symphalangism
Comment of the Author/Creator:Correspondence: Dr K Lehmann, Institut für Medinzische Genetik, Universitätsmedizin Berlin, Charité, Augustenburger Platz 1, Berlin 13353, Germany. Tel: +49 30 450 569132; Fax: +49 30 450 569914; e-mail:
External Publication Status:published
Document Type:Article
Communicated by:Stefan Mundlos
Affiliations:MPI für molekulare Genetik
External Affiliations:Institut für Medizinische Genetik, Charité, Universitätsmedizin Berlin, Berlin, Germany;
Institut für Chemie-Biochemie, Freie Universität Berlin, Berlin, Germany;
Unité de Génétique Clinique, Département de Pédiatrie, Amiens, France;
Institut für Humangenetik und Medizinische Biologie, Universität Halle/Saale, Germany
Relations:Has References-:10.1038/sj.ejhg.5201708
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