De Novo Mutations in SLC25A24 Cause a Disorder Characterized by Early Aging, Bone Dysplasia, Characteristic Face, and Early Demise

Karin Writzl 1, * Ales Maver 1 Lidija Kovačič 2 Paula Martinez-Valero 3, 4, 5 Laura Contreras 5, 3, 4 Jorgina Satrustegui 5, 3, 4 Marco Castori 6 Laurence Faivre 7, 8 Pablo Lapunzina 9 André B.P. Van Kuilenburg 10 Slobodanka Radović 11 Christel Thauvin-Robinet 7, 8 Borut Peterlin 1 Araceli Del Arco 12, 3, 4 Raoul C. Hennekam 13
Abstract : A series of simplex cases have been reported under various diagnoses sharing early aging, especially evident in congenitally decreased subcutaneous fat tissue and sparse hair, bone dysplasia of the skull and fingers, a distinctive facial gestalt, and prenatal and postnatal growth retardation. For historical reasons, we suggest naming the entity Fontaine syndrome. Exome sequencing of four unrelated affected individuals showed that all carried the de novo missense variant c.649C>T (p.Arg217Cys) or c.650G>A (p.Arg217His) in SLC25A24, a solute carrier 25 family member coding for calcium-binding mitochondrial carrier protein (SCaMC-1, also known as SLC25A24). SLC25A24 allows an electro-neutral and reversible exchange of ATP-Mg and phosphate between the cytosol and mitochondria, which is required for maintaining optimal adenine nucleotide levels in the mitochondrial matrix. Molecular dynamic simulation studies predict that p.Arg217Cys and p.Arg217His narrow the substrate cavity of the protein and disrupt transporter dynamics. SLC25A24-mutant fibroblasts and cells expressing p.Arg217Cys or p.Arg217His variants showed altered mitochondrial morphology, a decreased proliferation rate, increased mitochondrial membrane potential, and decreased ATP-linked mitochondrial oxygen consumption. The results suggest that the SLC25A24 mutations lead to impaired mitochondrial ATP synthesis and cause hyperpolarization and increased proton leak in association with an impaired energy metabolism. Our findings identify SLC25A24 mutations affecting codon 217 as the underlying genetic cause of human progeroid Fontaine syndrome.
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American Journal of Human Genetics, Elsevier (Cell Press), 2017, 101 (5), pp.844 - 855. 〈http://www.sciencedirect.com/science/article/pii/S0002929717303865?via%3Dihub〉. 〈10.1016/j.ajhg.2017.09.017〉
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https://hal-univ-bourgogne.archives-ouvertes.fr/hal-01635146
Contributeur : Lnc - Université de Bourgogne <>
Soumis le : mardi 14 novembre 2017 - 17:57:05
Dernière modification le : vendredi 8 juin 2018 - 14:50:25

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Karin Writzl, Ales Maver, Lidija Kovačič, Paula Martinez-Valero, Laura Contreras, et al.. De Novo Mutations in SLC25A24 Cause a Disorder Characterized by Early Aging, Bone Dysplasia, Characteristic Face, and Early Demise. American Journal of Human Genetics, Elsevier (Cell Press), 2017, 101 (5), pp.844 - 855. 〈http://www.sciencedirect.com/science/article/pii/S0002929717303865?via%3Dihub〉. 〈10.1016/j.ajhg.2017.09.017〉. 〈hal-01635146〉

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