1. De Novo Mutations in SLC25A24 Cause a Craniosynostosis Syndrome with Hypertrichosis, Progeroid Appearance, and Mitochondrial Dysfunction
- Author
-
Denise Horn, Penelope E. Bonnen, Anna Floriane Hennig, Marten Jäger, Fernando Scaglia, Bernd Wollnik, Stefan Mundlos, Christian Netzer, Markus Schuelke, Uwe Kornak, Beatrix Fauler, Luitgard Graul-Neumann, Namrata Saha, Holger Thiele, Peter Krawitz, Lara Segebrecht, Jochen Hecht, Nadja Ehmke, Thorsten Mielke, Gökhan Yigit, Rainer Koenig, Carlos A. Bacino, Friederike Hennig, Nicolai Adolphs, Janine Altmüller, Pilar L. Magoulas, Lukasz Smorag, Vera M. Kalscheuer, Peter Nürnberg, Ulrike Krüger, Björn Fischer-Zirnsak, and Esra Kılıç
- Subjects
0301 basic medicine ,Hypertrichosis ,Mitochondrion ,Microphthalmia ,Antiporters ,Cutis Laxa ,Craniofacial Abnormalities ,0302 clinical medicine ,Adenosine Triphosphate ,Progeria ,Exome ,Inner mitochondrial membrane ,Child ,Ductus Arteriosus, Patent ,Genetics (clinical) ,Growth Disorders ,Membrane Potential, Mitochondrial ,Fetal Growth Retardation ,3. Good health ,Mitochondria ,Premature aging ,Child, Preschool ,Female ,Gorlin-chaudhry-moss syndrome ,medicine.medical_specialty ,Mitochondrial DNA ,Adolescent ,Biology ,DNA, Mitochondrial ,Mitochondrial Proteins ,03 medical and health sciences ,Craniosynostoses ,Craniosynostosis ,Internal medicine ,Report ,Genetics ,medicine ,Humans ,Abnormalities, Multiple ,Cutis laxa ,SLC25A24 ,Calcium-Binding Proteins ,Infant ,Hydrogen Peroxide ,Fibroblasts ,medicine.disease ,Oxidative Stress ,030104 developmental biology ,Endocrinology ,Oxidative stress ,Mitochondrial swelling ,Mutation ,Lipoatrophy ,030217 neurology & neurosurgery - 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. N.E. is a participant in the Berlin Institute of Health Charité Clinician Scientist Program, funded by the Charité - Universitätsmedizin Berlin and the Berlin Institute of Health. S.M. was supported by grants from the Deutsche Forschungsgemeinschaft (DFG) and the Max Planck Foundation, B.W. was supported by grants from the DFG SFB1002 project D02, and B.F.-Z. was supported by a grant from the DFG (FI 2240/1-1). U.K. received funding from FP7-EU grant agreement no. 602300 (SYBIL) and the DFG Research Unit FOR 2165 (249509554). Research reported in this publication was supported by National Institute of Neurological Disorders and Stroke of the National Institutes of Health under award number R01NS08372 to P.E.B.
- Published
- 2017