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ADAMTSL2 mutations in geleophysic dysplasia demonstrate a role for ADAMTS-like proteins in TGF-β bioavailability regulation


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-β–binding protein 1. In addition, we observed a significant increase in total and active TGF-β 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-β signaling and may be the underlying mechanism of geleophysic dysplasia.

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Figure 1: Clinical and radiological manifestations of geleophysic dysplasia in individual 3.
Figure 2: Genetic mapping of the locus involved in geleophysic dysplasia.
Figure 3: In situ hybridization analysis of ADAMTSL2 mRNA expression in a human fetus at 35 weeks of gestation.
Figure 4: Functional consequences of ADAMTSL2 mutations.
Figure 5: Analysis of TGF-β signalling pathway in geleophysic dysplasia fibroblasts.

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We thank the Kazusa DNA Research Institute for providing the KIAA0605 cDNA. We thank J. Martinovic for her help. We also thank T. Arai and M. Papouin. The work presented here was supported by French National Research Agency (ANR) award R06215KS (to V.C.-D.), the Medical Research Foundation (FRM, to C.L.G.), US National Institutes of Health (NIH) award AR53890 (to S.S.A.), NIH award GM71679 (to D.S.G.) and NIH award HD22657 (to D.K.).

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Authors and Affiliations



C.L.G. designed the experiments; performed in situ hybridization, protein blot analysis (ADAMTSL2 and SMAD2), TGF-β assays and immunocytochemistry and wrote the manuscript. F.M.-P. and N.D. performed the sequence analysis. L.W.W. performed coimmunoprecipitation studies. C.P., Y.J.C., F.B., E.F., D.K., D.B. and M.L.M. provided clinical data; C.P.-S. performed electron microscopy analysis. G.G. and D.S.G. cloned expression LTBP-1 constructs. A.M. and S.S.A. wrote the manuscript. V.C.-D. provided clinical data, designed the experiments, oversaw all aspects of the research and wrote the manuscript.

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Correspondence to Valérie Cormier-Daire.

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Le Goff, C., Morice-Picard, F., Dagoneau, N. et al. ADAMTSL2 mutations in geleophysic dysplasia demonstrate a role for ADAMTS-like proteins in TGF-β bioavailability regulation. Nat Genet 40, 1119–1123 (2008).

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