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Free keywords:
Abnormalities, Multiple/*genetics
Adenosine Triphosphate/genetics
Adolescent
Antiporters/*genetics
Calcium-Binding Proteins/*genetics
Child
Child, Preschool
Craniofacial Abnormalities/*genetics
Craniosynostoses/*genetics
Cutis Laxa/genetics
DNA, Mitochondrial/genetics
Ductus Arteriosus, Patent/*genetics
Exome/genetics
Female
Fetal Growth Retardation/genetics
Fibroblasts/pathology
Humans
Hydrogen Peroxide/pharmacology
Hypertrichosis/*genetics
Infant
Membrane Potential, Mitochondrial/drug effects/genetics
Mitochondria/drug effects/*genetics
Mitochondrial Proteins/*genetics
Mutation/*genetics
Oxidative Stress/genetics
Progeria/genetics
Abstract:
Gorlin-Chaudhry-Moss syndrome (GCMS) is a dysmorphic syndrome characterized by coronal craniosynostosis and severe midface hypoplasia, body and facial hypertrichosis, microphthalmia, short stature, and short distal phalanges. Variable lipoatrophy and cutis laxa are the basis for a progeroid appearance. Using exome and genome sequencing, we identified the recurrent de novo mutations c.650G>A (p.Arg217His) and c.649C>T (p.Arg217Cys) in SLC25A24 in five unrelated girls diagnosed with GCMS. Two of the girls had pronounced neonatal progeroid features and were initially diagnosed with Wiedemann-Rautenstrauch syndrome. SLC25A24 encodes a mitochondrial inner membrane ATP-Mg/Pi carrier. In fibroblasts from affected individuals, the mutated SLC25A24 showed normal stability. In contrast to control cells, the probands' cells showed mitochondrial swelling, which was exacerbated upon treatment with hydrogen peroxide (H2O2). The same effect was observed after overexpression of the mutant cDNA. Under normal culture conditions, the mitochondrial membrane potential of the probands' fibroblasts was intact, whereas ATP content in the mitochondrial matrix was lower than that in control cells. However, upon H2O2 exposure, the membrane potential was significantly elevated in cells harboring the mutated SLC25A24. No reduction of mitochondrial DNA copy number was observed. These findings demonstrate that mitochondrial dysfunction with increased sensitivity to oxidative stress is due to the SLC25A24 mutations. Our results suggest that the SLC25A24 mutations induce a gain of pathological function and link mitochondrial ATP-Mg/Pi transport to the development of skeletal and connective tissue.
