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De Novo Mutations in SLC25A24 Cause a Craniosynostosis Syndrome with Hypertrichosis, Progeroid Appearance, and Mitochondrial Dysfunction.


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.

SUBMITTER: Ehmke N 

PROVIDER: S-EPMC5673623 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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De Novo Mutations in SLC25A24 Cause a Craniosynostosis Syndrome with Hypertrichosis, Progeroid Appearance, and Mitochondrial Dysfunction.

Ehmke Nadja N   Graul-Neumann Luitgard L   Smorag Lukasz L   Koenig Rainer R   Segebrecht Lara L   Magoulas Pilar P   Scaglia Fernando F   Kilic Esra E   Hennig Anna F AF   Adolphs Nicolai N   Saha Namrata N   Fauler Beatrix B   Kalscheuer Vera M VM   Hennig Friederike F   Altmüller Janine J   Netzer Christian C   Thiele Holger H   Nürnberg Peter P   Yigit Gökhan G   Jäger Marten M   Hecht Jochen J   Krüger Ulrike U   Mielke Thorsten T   Krawitz Peter M PM   Horn Denise D   Schuelke Markus M   Mundlos Stefan S   Bacino Carlos A CA   Bonnen Penelope E PE   Wollnik Bernd B   Fischer-Zirnsak Björn B   Kornak Uwe U  

American journal of human genetics 20171101 5


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 t  ...[more]

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