TY - JOUR
T1 - SLC10A7 mutations cause a skeletal dysplasia with amelogenesis imperfecta mediated by GAG biosynthesis defects
AU - Dubail, Johanne
AU - Huber, Céline
AU - Chantepie, Sandrine
AU - Sonntag, Stephan
AU - Tüysüz, 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, Valérie
N1 - Funding Information:
This work was supported by the European Community’s Seventh Framework Programme (FP7/2007-2013) under grant agreement number 602300 (SYBIL) and the Fondation pour la Recherche Médicale (FRM) funding (DEQ20120323703). We gratefully acknowledge Myriam Oufadem, the Genomic and Bioinformatic facilities of Institut Imagine for help in exome sequencing analyses, Morad Bensidhoum and SFR IMOSAR for μCT scans, Benjamin Fournier from Laboratory of Molecular Oral Pathophysiology (INSERM UMR_S1138) for scanning electron microscopy analysis, Barbara Vona and Thomas Haaf from Institute of Human Genetics of Julius Maximilians University Würzburg (Germany), Eric Hennekam from the department of genetics (University Medical Center, Utrecht) and the medical specialists in the UMC Utrecht Expert Center for Congenital Orofacial and Dental Anomalies for sharing patient data, and the Histology facility and the Imaging facility of SFR Necker. We thank Simon J. Foulcer for providing helpful comments on the manuscript.
Publisher Copyright:
© 2018, The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
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.
UR - https://www.scopus.com/pages/publications/85051279355
U2 - 10.1038/s41467-018-05191-8
DO - 10.1038/s41467-018-05191-8
M3 - Article
AN - SCOPUS:85051279355
SN - 2041-1723
VL - 9
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 3087
ER -