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Journal Article

GDF5 Is a Second Locus for Multiple-Synostosis Syndrome

MPS-Authors
http://pubman.mpdl.mpg.de/cone/persons/resource/persons50548

Seemann,  Petra
Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons50437

Mundlos,  Stefan
Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Dawson.pdf
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Citation

Dawson, K., Seemann, P., Sebald, E., King, L., Edwards, M., Williams III, J., et al. (2006). GDF5 Is a Second Locus for Multiple-Synostosis Syndrome. American Journal of Human Genetics (Chicago, IL), 78(4), 708-712.


Cite as: http://hdl.handle.net/11858/00-001M-0000-0010-8458-9
Abstract
Multiple-synostosis syndrome is an autosomal dominant disorder characterized by progressive symphalangism, carpal/tarsal fusions, deafness, and mild facial dysmorphism. Heterozygosity for functional null mutations in the NOGGIN gene has been shown to be responsible for the disorder. However, in a cohort of six probands with multiple-synostosis syndrome, only one was found to be heterozygous for a NOGGIN mutation (W205X). Linkage studies involving the four-generation family of one of the mutation-negative patients excluded the NOGGIN locus, providing genetic evidence of locus heterogeneity. In this family, polymorphic markers flanking the GDF5 locus were found to cosegregate with the disease, and sequence analysis demonstrated that affected individuals in the family were heterozygous for a novel missense mutation that predicts an R438L substitution in the GDF5 protein. Unlike mutations that lead to haploinsufficiency for GDF5 and produce brachydactyly C, the protein encoded by the multiple-synostosis–syndrome allele was secreted as a mature GDF5 dimer. These data establish locus heterogeneity in multiple-synostosis syndrome and demonstrate that the disorder can result from mutations in either the NOGGIN or the GDF5 gene.