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The mutational spectrum of brachydactyly type C

2002; Wiley; Volume: 112; Issue: 3 Linguagem: Inglês

10.1002/ajmg.10777

1096-8628

David B. Everman, Cynthia F. Bartels, Yue Yang, Niranjan Yanamandra, Frances R. Goodman, Roberto Mendoza‐Londono, Ravi Savarirayan, Susan M. White, John M. Graham, Robert Peter Gale, Eva Svarch, William G. Newman, Albert R. Kleckers, Clair A. Francomano, Govindaiah Vinukonda, Lalji Singh, Stuart Morrison, J. Terrig Thomas, Matthew L. Warman,

TGF-β signaling in diseases

Abstract Growth/differentiation factor‐5 (GDF5), also known as cartilage‐derived morphogenetic protein‐1 (CDMP‐1), is a secreted signaling molecule that participates in skeletal morphogenesis. Heterozygous mutations in GDF5 , which maps to human chromosome 20, occur in individuals with autosomal dominant brachydactyly type C (BDC). Here we show that BDC is locus homogeneous by reporting a GDF5 frameshift mutation segregating with the phenotype in a family whose trait was initially thought to map to human chromosome 12. We also describe heterozygous mutations in nine additional probands/families with BDC and show nonpenetrance in a mutation carrier. Finally, we show that mutant GDF5 polypeptides containing missense mutations in their active domains do not efficiently form disulfide‐linked dimers when expressed in vitro. These data support the hypothesis that BDC results from functional haploinsufficiency for GDF5. © 2002 Wiley‐Liss, Inc.