De novo mutations in SLC25A24 cause a craniosynostosis syndrome with hypertrichosis, progeroid appearance, and mitochondrial dysfunction

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• dc.contributor.author Ehmke, Nadjaca
• dc.contributor.author Hecht, Jochenca
• dc.contributor.author Kornak, Uweca
• dc.date.accessioned 2018-05-16T09:18:47Z
• dc.date.available 2018-05-16T09:18:47Z
• dc.date.issued 2017
• dc.description.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.
• dc.description.sponsorship 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.
• dc.format.mimetype application/pdf
• dc.identifier.citation Ehmke N, Graul-Neumann L, Smorag L, Koenig R, Segebrecht L, Magoulas P et al. De Novo Mutations in SLC25A24 Cause a Craniosynostosis Syndrome with Hypertrichosis, Progeroid Appearance, and Mitochondrial Dysfunction. Am J Hum Genet. 2017 Nov;101(5):833-43. DOI: 10.1016/j.ajhg.2017.09.016
• dc.identifier.doi http://dx.doi.org/10.1016/j.ajhg.2017.09.016
• dc.identifier.issn 0002-9297
• dc.identifier.uri http://hdl.handle.net/10230/34644
• dc.language.iso eng
• dc.publisher Elsevierca
• dc.relation.ispartof American Journal of Human Genetics. 2017 Nov;101(5):833-43
• dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/602300
• dc.rights © Elsevier This is the published version of an article http://dx.doi.org/10.1016/j.ajhg.2017.09.016 that appeared in the journal Am J Hum Genet. It is published in an Open Archive under an Elsevier user license. Details of this licence are available here: https://www.elsevier.com/about/our-business/policies/open-access-licenses/elsevier-user-license
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.subject.keyword Gorlin-chaudhry-moss syndrome
• dc.subject.keyword SLC25A24
• dc.subject.keyword Craniosynostosis
• dc.subject.keyword Cutis laxa
• dc.subject.keyword Hypertrichosis
• dc.subject.keyword Lipoatrophy
• dc.subject.keyword Mitochondrial swelling
• dc.subject.keyword Oxidative stress
• dc.subject.keyword Premature aging
• dc.title De novo mutations in SLC25A24 cause a craniosynostosis syndrome with hypertrichosis, progeroid appearance, and mitochondrial dysfunctionca
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion