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

Ehmke, N., Graul-Neumann, L., Smorag, L., Koenig, R., Segebrecht, L., Magoulas, P., et al. (2017). De Novo Mutations in SLC25A24 Cause a Craniosynostosis Syndrome with Hypertrichosis, Progeroid Appearance, and Mitochondrial Dysfunction. The American Journal of Human Genetics, 101(5), 833-843. doi:10.1016/j.ajhg.2017.09.016.

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© 2017 American Society of Human Genetics
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http://www.ncbi.nlm.nih.gov/pubmed/29100093 (beliebiger Volltext)
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 Urheber:
Ehmke, N., Autor
Graul-Neumann, L., Autor
Smorag, L., Autor
Koenig, R., Autor
Segebrecht, L., Autor
Magoulas, P., Autor
Scaglia, F., Autor
Kilic, E., Autor
Hennig, A. F., Autor
Adolphs, N., Autor
Saha, N., Autor
Fauler, B.1, Autor           
Kalscheuer, V. M.2, Autor           
Hennig, F.2, Autor           
Altmüller, J., Autor
Netzer, C., Autor
Thiele, H., Autor
Nürnberg, P., Autor
Yigit, G., Autor
Jäger, M., Autor
Hecht, J., AutorKrüger, U., AutorMielke, T., AutorKrawitz, P. M., AutorHorn, D., AutorSchuelke, M., AutorMundlos, S.3, Autor           Bacino, C. A., AutorBonnen, P. E., AutorWollnik, B., AutorFischer-Zirnsak, B., AutorKornak, U.3, Autor            mehr..
Affiliations:
1Microscopy and Cryo-Electron Microscopy (Head: Thorsten Mielke), Scientific Service (Head: Christoph Krukenkamp), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479668              
2Chromosome Rearrangements and Disease (Vera Kalscheuer), Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2385702              
3Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433557              

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Schlagwörter: 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
 Zusammenfassung: 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.

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Sprache(n): eng - English
 Datum: 2017-11-02
 Publikationsstatus: Erschienen
 Seiten: 11
 Ort, Verlag, Ausgabe: -
 Inhaltsverzeichnis: -
 Art der Begutachtung: -
 Identifikatoren: DOI: 10.1016/j.ajhg.2017.09.016
ISSN: 1537-6605 (Electronic)0002-9297 (Print)
 Art des Abschluß: -

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Titel: The American Journal of Human Genetics
  Andere : Am. J. Hum. Genet.
Genre der Quelle: Zeitschrift
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Ort, Verlag, Ausgabe: American Society of Human Genetics
Seiten: - Band / Heft: 101 (5) Artikelnummer: - Start- / Endseite: 833 - 843 Identifikator: ISSN: 0002-9297
CoNE: https://pure.mpg.de/cone/journals/resource/954925377893_1