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

Johanne Dubail, Céline Huber, Sandrine Chantepie, Stephan Sonntag, Beyhan Tüysüz, Ercan Mihci, Christopher T. Gordon, Elisabeth Steichen-Gersdorf, Jeanne Amiel, Banu Nur, Irene Stolte-Dijkstra, Albertien M. Eerde, Koen L. Gassen, Corstiaan C. Breugem, Alexander Stegmann, Caroline Lekszas, Reza Maroofian, Ehsan Ghayoor Karimiani, Arnaud Bruneel, Nathalie Seta, Arnold Munnich, Dulce Papy-Garcia, Muriel Dure-Molla and Valérie Cormier-Daire ()
Additional contact information
Johanne Dubail: INSERM UMR 1163, Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, AP-HP, Hôpital Necker Enfants Malades
Céline Huber: INSERM UMR 1163, Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, AP-HP, Hôpital Necker Enfants Malades
Sandrine Chantepie: Université Paris-Est Créteil, EA 4397 CNRS 9215
Stephan Sonntag: PolyGene AG
Beyhan Tüysüz: Istanbul University
Ercan Mihci: Akdeniz University Paediatric Genetic Deaprtment
Christopher T. Gordon: Laboratory of Embryology and Genetics of Congenital Malformations, INSERM UMR 1163, Institut Imagine
Elisabeth Steichen-Gersdorf: Medical University of Innsbruck
Jeanne Amiel: Laboratory of Embryology and Genetics of Congenital Malformations, INSERM UMR 1163, Institut Imagine
Banu Nur: Istanbul University
Irene Stolte-Dijkstra: University Medical Center Groningen, University of Groningen
Albertien M. Eerde: University Medical Center Utrecht
Koen L. Gassen: University Medical Center Utrecht
Corstiaan C. Breugem: Wilhelmina Children´s Hopsital
Alexander Stegmann: Radboud University Medical Center
Caroline Lekszas: Julius Maximilians University Würzburg
Reza Maroofian: St George’s, University of London, Cranmer Terrace
Ehsan Ghayoor Karimiani: St George’s, University of London, Cranmer Terrace
Arnaud Bruneel: Hôpital Bichat
Nathalie Seta: Hôpital Bichat
Arnold Munnich: INSERM UMR 1163, Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, AP-HP, Hôpital Necker Enfants Malades
Dulce Papy-Garcia: Université Paris-Est Créteil, EA 4397 CNRS 9215
Muriel Dure-Molla: INSERM UMR 1163, Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, AP-HP, Hôpital Necker Enfants Malades
Valérie Cormier-Daire: INSERM UMR 1163, Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, AP-HP, Hôpital Necker Enfants Malades

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-05191-8

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