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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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Item Permalink: http://hdl.handle.net/21.11116/0000-0000-CE88-F Version Permalink: http://hdl.handle.net/21.11116/0000-0002-5988-1
Genre: Journal Article

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© 2017 American Society of Human Genetics
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 Creators:
Ehmke, N., Author
Graul-Neumann, L., Author
Smorag, L., Author
Koenig, R., Author
Segebrecht, L., Author
Magoulas, P., Author
Scaglia, F., Author
Kilic, E., Author
Hennig, A. F., Author
Adolphs, N., Author
Saha, N., Author
Fauler, B.1, Author              
Kalscheuer, V. M.2, Author              
Hennig, F.2, Author              
Altmüller, J., Author
Netzer, C., Author
Thiele, H., Author
Nürnberg, P., Author
Yigit, G., Author
Jäger, M., Author
Hecht, J., AuthorKrüger, U., AuthorMielke, T., AuthorKrawitz, P. M., AuthorHorn, D., AuthorSchuelke, M., AuthorMundlos, S.3, Author              Bacino, C. A., AuthorBonnen, P. E., AuthorWollnik, B., AuthorFischer-Zirnsak, B., AuthorKornak, U.3, Author               more..
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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Free keywords: 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
 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.

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Language(s): eng - English
 Dates: 2017-11-02
 Publication Status: Published in print
 Pages: 11
 Publishing info: -
 Table of Contents: -
 Rev. Method: -
 Identifiers: DOI: 10.1016/j.ajhg.2017.09.016
ISSN: 1537-6605 (Electronic)0002-9297 (Print)
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Title: The American Journal of Human Genetics
  Other : Am. J. Hum. Genet.
Source Genre: Journal
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Publ. Info: American Society of Human Genetics
Pages: - Volume / Issue: 101 (5) Sequence Number: - Start / End Page: 833 - 843 Identifier: ISSN: 0002-9297
CoNE: /journals/resource/954925377893_1