title: ADAMTS10 mutations in autosomal recessive Weill-Marchesani syndrome.
abstract: Weill-Marchesani syndrome (WMS) is characterized by the association of short stature; brachydactyly; joint stiffness; eye anomalies, including microspherophakia and ectopia of the lenses; and, occasionally, heart defects. We have recently mapped a gene for the autosomal recessive form of WMS to chromosome 19p13.3-p13.2, in a 12.4-cM interval. Here, we report null mutations in a member of the extracellular matrix protease family, the gene encoding ADAMTS10, a disintegrin and metalloprotease with thrombospondin motifs. A total of three distinct mutations were identified in two consanguineous families and in one sporadic WMS case, including one nonsense mutation (R237X) and two splice mutations (1190+1G-->A and 810+1G-->A). ADAMTS10 expression studies using reverse-transcriptase polymerase chain reaction, northern blot, and dot-blot analyses showed that ADAMTS10 is expressed in skin, fetal chondrocytes, and fetal and adult heart. Moreover, electron microscopy and immunological studies of the skin fibroblasts from the patients confirmed impairment of the extracellular matrix. We conclude, therefore, that ADAMTS10 plays a major role in growth and in skin, lens, and heart development in humans.
authors.affiliation: Department of Genetics and INSERM U393, Hopital Necker Enfants Malades, Paris, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Dagoneau
authors.forename: Catherine
authors.initials: C
authors.lastname: Benoist-Lasselin
authors.forename: Céline
authors.initials: C
authors.lastname: Huber
authors.forename: Laurence
authors.initials: L
authors.lastname: Faivre
authors.forename: André
authors.initials: A
authors.lastname: Mégarbané
authors.forename: Abdulrahman
authors.initials: A
authors.lastname: Alswaid
authors.forename: Hélène
authors.initials: H
authors.lastname: Dollfus
authors.forename: Yves
authors.initials: Y
authors.lastname: Alembik
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Laurence
authors.initials: L
authors.lastname: Legeai-Mallet
authors.forename: Valérie
authors.initials: V
authors.lastname: Cormier-Daire
mesh_terms: D051722:ADAM Proteins; D000071096:ADAMTS Proteins; D000015:Abnormalities, Multiple / Q000235:genetics*; D000199:Actins / Q000378:metabolism; D001483:Base Sequence; D015152:Blotting, Northern; D002648:Child; D017931:DNA Primers; D004392:Dwarfism / Q000235:genetics; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D005124:Eye Abnormalities / Q000235:genetics; D005347:Fibroblasts / Q000276:immunology / Q000648:ultrastructure; D040461:Gene Components; D015870:Gene Expression; D005808:Genes, Recessive / Q000235:genetics; D006801:Humans; D015151:Immunoblotting; D008666:Metalloendopeptidases / Q000235:genetics; D008854:Microscopy, Electron; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010375:Pedigree; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D013577:Syndrome
chemical_list: D000199:Actins; D017931:DNA Primers; D016326:Extracellular Matrix Proteins; D051722:ADAM Proteins; D000071096:ADAMTS Proteins; C494614:ADAMTS10 protein, human; D008666:Metalloendopeptidases