ADAMTSL2 mutations in geleophysic dysplasia demonstrate a role for ADAMTS-like proteins in TGF-beta 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-beta-binding protein 1. In addition, we observed a significant increase in total and active TGF-beta 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-beta signaling and may be the underlying mechanism of geleophysic dysplasia.
Le Goff
Carine
C
Département de Génétique, Unité INSERM U781, Université Paris Descartes, Assistance Publique-Hôpitaux de Paris, Hôpital Necker-Enfants Malades, 75015 Paris, France.
Morice-Picard
Fanny
F
Dagoneau
Nathalie
N
Wang
Lauren W
LW
Perrot
Claire
C
Crow
Yanick J
YJ
Bauer
Florence
F
Flori
Elisabeth
E
Prost-Squarcioni
Catherine
C
Krakow
Deborah
D
Ge
Gaoxiang
G
Greenspan
Daniel S
DS
Bonnet
Damien
D
Le Merrer
Martine
M
Munnich
Arnold
A
Apte
Suneel S
SS
Cormier-Daire
Valérie
V
D000015:Abnormalities, Multiple / Q000235:genetics*; D001682:Biological Availability; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D006130:Growth Disorders / Q000235:genetics*; D006228:Hand Deformities, Congenital / Q000235:genetics; D006330:Heart Defects, Congenital / Q000235:genetics; D006351:Heart Valves / Q000002:abnormalities*; D006801:Humans; D009154:Mutation; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D016326:Extracellular Matrix Proteins; D016212:Transforming Growth Factor beta