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



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ID: 313082.0, MPI für molekulare Genetik / Research Group Development and Disease
GDF5 Is a Second Locus for Multiple-Synostosis Syndrome
Authors:Dawson, Katherine; Seemann, Petra; Sebald, Eiman; King, Lily; Edwards, Matthew; Williams III, John; Mundlos, Stefan; Krakow, Deborah
Language:English
Date of Publication (YYYY-MM-DD):2006-04
Title of Journal:American Journal of Human Genetics (Chicago, IL)
Journal Abbrev.:Am J Hum Genet
Volume:78
Issue / Number:4
Start Page:708
End Page:712
Copyright:© 2006 by The American Society of Human Genetics
Review Status:not specified
Audience:Experts Only
Abstract / Description: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.
External Publication Status:published
Document Type:Article
Version Comment:Automatic journal name synchronization
Communicated by:Stefan Mundlos
Affiliations:MPI für molekulare Genetik
External Affiliations:Kaiser Permanente, Oakland, CA;
Institute of Medical Genetics, Charite Universtatsmedizin, Berlin;
Medical Genetics Institute, 5Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center and David Geffen School of Medicine, University of California–Los Angeles, Los Angeles;
Hunter Genetics, Hunter Area Health Service, University of Newcastle, Waratah, Australia
Identifiers:ISSN:0002-9297
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