Letter abstract
Nature Genetics 40, 1119 - 1123 (2008)
Published online: 1 August 2008 | doi:10.1038/ng.199
ADAMTSL2 mutations in geleophysic dysplasia demonstrate a role for ADAMTS-like proteins in TGF-
bioavailability regulation
Carine Le Goff1, Fanny Morice-Picard1,10, Nathalie Dagoneau1,10, Lauren W Wang2, Claire Perrot1, Yanick J Crow3, Florence Bauer4, Elisabeth Flori5, Catherine Prost-Squarcioni6, Deborah Krakow7, Gaoxiang Ge8, Daniel S Greenspan8, Damien Bonnet9, Martine Le Merrer1, Arnold Munnich1, Suneel S Apte2 & Valérie Cormier-Daire1
Geleophysic dysplasia is an autosomal recessive disorder characterized by short stature, brachydactyly, thick skin and cardiac valvular anomalies often responsible for an early death. Studying six geleophysic dysplasia families, we first mapped the underlying gene to chromosome 9q34.2 and identified five distinct nonsense and missense mutations in ADAMTSL2 (a disintegrin and metalloproteinase with thrombospondin repeats–like 2), which encodes a secreted glycoprotein of unknown function. Functional studies in HEK293 cells showed that ADAMTSL2 mutations lead to reduced secretion of the mutated proteins, possibly owing to the misfolding of ADAMTSL2. A yeast two-hybrid screen showed that ADAMTSL2 interacts with latent TGF-
–binding protein 1. In addition, we observed a significant increase in total and active TGF- in the culture medium as well as nuclear localization of phosphorylated SMAD2 in fibroblasts from individuals with geleophysic dysplasia. These data suggest that ADAMTSL2 mutations may lead to a dysregulation of TGF- signaling and may be the underlying mechanism of geleophysic dysplasia.
- Département de Génétique, Unité INSERM U781, Université Paris Descartes, Assistance Publique-Hôpitaux de Paris, Hôpital Necker-Enfants Malades, 75015 Paris, France.
- Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
- Leeds Institute of Molecular Medicine, St James's University Hospital, LS29JT Leeds, UK.
- Clinique Paofaï, Fare Tony, Papeete, Tahiti.
- Département de Génétique, Hôpital de Hautepierre, Strasbourg 67000, France.
- CNRS UPRES 3410, Faculté de Médecine, Hôpital Avicennes, 93000 Bobigny, France.
- Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.
- Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, Wisconsin 53706, USA.
- Service de Cardiologie Pédiatrique, Hôpital Necker-Enfants Malades, 75015 Paris, France.
- These authors contributed equally to this work.
Correspondence to: Valérie Cormier-Daire1 e-mail: valerie.cormier-daire@inserm.fr
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