TY - JOUR
T1 - SLC10A7 mutations cause a skeletal dysplasia with amelogenesis imperfecta mediated by GAG biosynthesis defects
AU - Dubail, Johanne
AU - Huber, Celine
AU - Chantepie, Sandrine
AU - Sonntag, Stephan
AU - Tuysuz, Beyhan
AU - Mihci, Ercan
AU - Gordon, Christopher T.
AU - Steichen-Gersdorf, Elisabeth
AU - Amiel, Jeanne
AU - Nur, Banu
AU - Stolte-Dijkstra, Irene
AU - van Eerde, Albertien M.
AU - van Gassen, Koen L.
AU - Breugem, Corstiaan C.
AU - Stegmann, Alexander
AU - Lekszas, Caroline
AU - Maroofian, Reza
AU - Karimiani, Ehsan Ghayoor
AU - Bruneel, Arnaud
AU - Seta, Nathalie
AU - Munnich, Arnold
AU - Papy-Garcia, Dulce
AU - De La Dure-Molla, Muriel
AU - Cormier-Daire, Valerie
PY - 2018/8/6
Y1 - 2018/8/6
N2 - 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.
AB - 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.
KW - HEPARAN-SULFATE PROTEOGLYCANS
KW - GROWTH-PLATE
KW - GENE
KW - CHONDROITIN
KW - CALCIUM
KW - GLYCOSAMINOGLYCANS
KW - PHENOTYPES
KW - DISORDERS
KW - REGULATOR
KW - PROTEINS
U2 - 10.1038/s41467-018-05191-8
DO - 10.1038/s41467-018-05191-8
M3 - Article
C2 - 30082715
SN - 2041-1723
VL - 9
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 3087
ER -