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

Nat Commun. 2018 Aug 6;9(1):3087. doi: 10.1038/s41467-018-05191-8.

Johanne Dubail ¹, Céline Huber ¹, Sandrine Chantepie ², Stephan Sonntag ³, Beyhan Tüysüz ⁴, Ercan Mihci ⁵, Christopher T Gordon ⁶, Elisabeth Steichen-Gersdorf ⁷, Jeanne Amiel ⁶, Banu Nur ⁴, Irene Stolte-Dijkstra ⁸, Albertien M van Eerde ⁹, Koen L van Gassen ⁹, Corstiaan C Breugem ¹⁰, Alexander Stegmann ¹¹ ¹², Caroline Lekszas ¹³, Reza Maroofian ¹⁴, Ehsan Ghayoor Karimiani ¹⁴ ¹⁵ ¹⁶, Arnaud Bruneel ¹⁷, Nathalie Seta ¹⁷, Arnold Munnich ¹, Dulce Papy-Garcia ², Muriel De La Dure-Molla ¹ ¹⁸, Valérie Cormier-Daire ¹⁹

Affiliations

1 Department of Genetics, INSERM UMR 1163, Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, AP-HP, Hôpital Necker Enfants Malades, 75015 Paris, France.
2 Cell Growth and Tissue Repair CRRET Laboratory, Université Paris-Est Créteil, EA 4397 CNRS 9215, Créteil, F-94010, France.
3 PolyGene AG, Rümlang, CH-8153, Switzerland.
4 Department of Pediatric Genetics, Cerrahpasa Medicine School, Istanbul University, 34290 Istanbul, Turkey.
5 Akdeniz University Paediatric Genetic Deaprtment, 07059 Antalya, Turkey.
6 Laboratory of Embryology and Genetics of Congenital Malformations, INSERM UMR 1163, Institut Imagine, 75015 Paris, France.
7 Department of Paediatrics I, Medical University of Innsbruck, A-6020 Innsbruck, Austria.
8 Department of Genetics, University Medical Center Groningen, University of Groningen, 9700 Groningen, The Netherlands.
9 Department of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, 3508 Utrecht, The Netherlands.
10 Division of Paediatric Plastic Surgery, Wilhelmina Children´s Hopsital, 3584 Utrecht, The Netherlands.
11 Department of Human Genetics, Radboud University Medical Center, 6525 Nijmegen, The Netherlands.
12 Department of Clinical Genetics, Maastricht University Medical Center, 6202 Maastricht, The Netherlands.
13 Institute of Human Genetics, Julius Maximilians University Würzburg, 97074 Würzburg, Germany.
14 Genetics Research Centre, Molecular and Clinical Sciences Institute, St George's, University of London, Cranmer Terrace, London SW17 ORE, UK.
15 Next Generation Genetic Clinic, 9175954353 Mashhad, Iran.
16 Razavi Cancer Research Center, Razavi Hospital, Imam Reza International University, 9198613636 Mashhad, Iran.
17 AP-HP, Biochimie Métabolique et cellulaire, Hôpital Bichat, 75018 Paris, France.
18 Laboratory of Molecular Oral Pathophysiology, Centre de Recherche des Cordeliers, INSERM UMRS 1138, University Paris-Descartes, University Pierre et Marie Curie-Paris, 75006 Paris, France.
19 Department of Genetics, INSERM UMR 1163, Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, AP-HP, Hôpital Necker Enfants Malades, 75015 Paris, France. valerie.cormier-daire@inserm.fr.

PMID: 30082715 DOI: 10.1038/s41467-018-05191-8

Abstract

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.

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