Ehmke, Nadja, Graul-Neumann, Luitgard, Smorag, Lukasz, Koenig, Rainer, Segebrecht, Lara ORCID: 0000-0002-0939-3213, Magoulas, Pilar, Scaglia, Fernando, Kilic, Esra, Hennig, Anna F., Adolphs, Nicolai, Saha, Namrata, Fauler, Beatrix, Kalscheuer, Vera M., Hennig, Friederike, Altmueller, Janine, Netzer, Christian, Thiele, Holger, Nuernberg, Peter, Yigit, Goekhan, Jaeger, Marten, Hecht, Jochen, Krueger, Ulrike, Mielke, Thorsten, Krawitz, Peter M., Horn, Denise, Schuelke, Markus ORCID: 0000-0003-2824-3891, Mundlos, Stefan, Bacino, Carlos A., Bonnen, Penelope E., Wollnik, Bernd, Fischer-Zirnsak, Bjoern and Kornak, Uwe (2017). De Novo Mutations in SLC25A24 Cause a Craniosynostosis Syndrome with Hypertrichosis, Progeroid Appearance, and Mitochondrial Dysfunction. Am. J. Hum. Genet., 101 (5). S. 833 - 844. CAMBRIDGE: CELL PRESS. ISSN 1537-6605

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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/P-i transport to the development of skeletal and connective tissue.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Ehmke, NadjaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Graul-Neumann, LuitgardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Smorag, LukaszUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koenig, RainerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Segebrecht, LaraUNSPECIFIEDorcid.org/0000-0002-0939-3213UNSPECIFIED
Magoulas, PilarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Scaglia, FernandoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kilic, EsraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hennig, Anna F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Adolphs, NicolaiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Saha, NamrataUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fauler, BeatrixUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kalscheuer, Vera M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hennig, FriederikeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Altmueller, JanineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Netzer, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thiele, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuernberg, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yigit, GoekhanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jaeger, MartenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hecht, JochenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Krueger, UlrikeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mielke, ThorstenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Krawitz, Peter M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Horn, DeniseUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schuelke, MarkusUNSPECIFIEDorcid.org/0000-0003-2824-3891UNSPECIFIED
Mundlos, StefanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bacino, Carlos A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bonnen, Penelope E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wollnik, BerndUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fischer-Zirnsak, BjoernUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kornak, UweUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-211570
DOI: 10.1016/j.ajhg.2017.09.016
Journal or Publication Title: Am. J. Hum. Genet.
Volume: 101
Number: 5
Page Range: S. 833 - 844
Date: 2017
Publisher: CELL PRESS
Place of Publication: CAMBRIDGE
ISSN: 1537-6605
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
GORLIN-CHAUDHRY-MOSS; CA-2&-INDUCED MEMBRANE TRANSITION; PERMEABILITY TRANSITION; CRANIOFACIAL DYSOSTOSIS; TRANSCRIPTION FACTOR; TWIST; GENE; ROLES; HYPOPLASIA; FRAMEWORKMultiple languages
Genetics & HeredityMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/21157

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