2. Academic Validation
  3. De Novo Mutations in SLC25A24 Cause a Disorder Characterized by Early Aging, Bone Dysplasia, Characteristic Face, and Early Demise

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

  • Am J Hum Genet. 2017 Nov 2;101(5):844-855. doi: 10.1016/j.ajhg.2017.09.017.
Karin Writzl 1,  Ales Maver 2,  Lidija Kovačič 3,  Paula Martinez-Valero 4,  Laura Contreras 4,  Jorgina Satrustegui 4,  Marco Castori 5,  Laurence Faivre 6,  Pablo Lapunzina 7,  André B P van Kuilenburg 8,  Slobodanka Radović 9,  Christel Thauvin-Robinet 6,  Borut Peterlin 2,  Araceli Del Arco 10,  Raoul C Hennekam 11
Affiliations

Affiliations

  • 1 Clinical Institute of Medical Genetics, University Medical Centre, 1000 Ljubljana, Slovenia. Electronic address: [email protected].
  • 2 Clinical Institute of Medical Genetics, University Medical Centre, 1000 Ljubljana, Slovenia.
  • 3 Novartis Ireland Ltd., Novartis, Vista Building, Elm Business Park, D04A9N6 Dublin 4, Ireland.
  • 4 Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid and Consejo Superior de Investigaciones Científicas, 28049 Madrid, Spain; Instituto de Investigación Sanitaria Fundación Jiménez Diaz, 28049 Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras, Instituto de Salud Carlos III, 28049 Madrid, Spain.
  • 5 Division of Medical Genetics, Casa Sollievo della Sofferenza, Istituto di Ricovero e Cura a Carattere Scientifico, 71013 San Giovanni Rotondo, Foggia, Italy.
  • 6 Centre de Référence Maladies Rares "cAnomalies du Développement et Syndromes Malformatifsc," Centre de Génétique, FHU-TRANSLAD, Hôpital d'Enfants, Centre Hospitalier Universitaire Dijon Bourgogne, 21079 Dijon, France; UMR 1231, Génétique des Anomalies du Développement, INSERM, Université de Bourgogne Franche-Comté, 21079 Dijon, France.
  • 7 Instituto de Genética Médica y Molecular-IdiPAZ, Hospital Universitario La Paz, Centro de Investigación Biomédica en Red de Enfermedades Raras, 261-28046 Madrid, Spain.
  • 8 Laboratory Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands.
  • 9 IGA Technology Services Srl., 33100 Udine, Italy.
  • 10 Instituto de Investigación Sanitaria Fundación Jiménez Diaz, 28049 Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras, Instituto de Salud Carlos III, 28049 Madrid, Spain; Facultad de Ciencias Ambientales y Bioquímica, Centro Regional de Investigaciones Biomédicas, Universidad de Castilla la Mancha, 45071-Toledo, Spain.
  • 11 Department of Pediatrics, Academic Medical Center, University of Amsterdam, 1105AZ Amsterdam, the Netherlands.
PMID: 29100094 DOI: 10.1016/j.ajhg.2017.09.017
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.

Keywords

ATP-Mg/Pi carriers; Petty syndrome; SCaMC-1; SLC25A24; aging; lipodystrophy; progeria; progeroid disorder.

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