Journal Article

SLC10A7 mutations cause a skeletal dysplasia with amelogenesis imperfecta mediated by GAG biosynthesis defects

Cormier-Daire, Valérie, Nur, Banu, De La Dure-Molla, Muriel, van Gassen, Koen L., Sonntag, Stephan, van Eerde, Albertien M., Tüysüz, Beyhan, Steichen-Gersdorf, Elisabeth, Dubail, Johanne, Mihci, Ercan, Huber, Céline, Lekszas, Caroline, Papy-Garcia, Dulce, Breugem, Corstiaan C., Bruneel, Arnaud, Maroofian, Reza, Karimiani, Ehsan Ghayoor, Stolte-Dijkstra, Irene, Amiel, Jeanne, Munnich, Arnold, Chantepie, Sandrine, Gordon, Christopher T., Stegmann, Alexander, Seta, Nathalie

2018

Overview

Skeletal dysplasia with multiple dislocations are severe disorders characterized by dislocations of large joints and short stature. The majority of them have been linked to pathogenic variants in genes encoding glycosyltransferases, sulfotransferases or epimerases required for glycosaminoglycan synthesis. Using exome sequencing, we identify homozygous mutations in SLC10A7 in six individuals with skeletal dysplasia with multiple dislocations and amelogenesis imperfecta. SLC10A7 encodes a 10-transmembrane-domain transporter located at the plasma membrane. Functional studies in vitro demonstrate that SLC10A7 mutations reduce SLC10A7 protein expression. We generate a Slc10a7 −/− mouse model, which displays shortened long bones, growth plate disorganization and tooth enamel anomalies, recapitulating the human phenotype. Furthermore, we identify decreased heparan sulfate levels in Slc10a7 −/− mouse cartilage and patient fibroblasts. Finally, we find an abnormal N -glycoprotein electrophoretic profile in patient blood samples. Together, our findings support the involvement of SLC10A7 in glycosaminoglycan synthesis and specifically in skeletal development. The majority of skeletal dysplasia are caused by pathogenic variants in genes required for glycosaminoglycan (GAG) metabolism. Here, Dubail et al. identify genetic variants in the solute carrier family protein SLC10A7 in families with skeletal dysplasia and amelogenesis imperfecta that disrupt GAG synthesis.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 14/32 / 38/1 / 38/23 / 631/136/818 / 631/208/1516 / 64/60 / 692/420/2489/144 / Amelogenesis imperfecta / Amelogenesis Imperfecta - genetics / Animals / Biosynthesis / Body Weight / Bone Diseases, Developmental - genetics / Bone dysplasia / Bones / Cartilage / Cercopithecus aethiops / Child / Child, Preschool / COS Cells / Dental enamel / Disease Models, Animal / Dislocations / Electrophoresis / Exome / Fibroblasts / Glycoproteins / Glycoproteins - chemistry / Growth plate / HEK293 Cells / Heparan sulfate / Humanities and Social Sciences / Humans / Infant / Life Sciences / Mice / Mice, Knockout / multidisciplinary / Mutation / Organic Anion Transporters, Sodium-Dependent - genetics / Osteochondrodysplasias - genetics / Phenotypes / Proteins / Science / Science (multidisciplinary) / Skeleton / Symporters - genetics / Teeth