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.; Scaglia, F.; Kilic, E.; Hennig, A. F.; Adolphs, N.; Saha, N.; Fauler, B.; Kalscheuer, V. M.; Hennig, F.; Altmüller, J.; Netzer, C.; Thiele, H.; Nürnberg, P.; Yigit, G.; Jäger, M.; Hecht, J.; Krüger, U.; Mielke, T.; Krawitz, P. M.; Horn, D.; Schuelke, M.; Mundlos, S.; Bacino, C. A.; Bonnen, P. E.; Wollnik, B.; Fischer-Zirnsak, B.; Kornak, U.

doi:10.1016/j.ajhg.2017.09.016

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., Scaglia, F., Kilic, E., Hennig, A. F., Adolphs, N., Saha, N., Fauler, B., Kalscheuer, V. M., Hennig, F., Altmüller, J., Netzer, C., Thiele, H., Nürnberg, P., Yigit, G., Jäger, M., Hecht, J., Krüger, U., Mielke, T., Krawitz, P. M., Horn, D., Schuelke, M., Mundlos, S., Bacino, C. A., Bonnen, P. E., Wollnik, B., Fischer-Zirnsak, B., & Kornak, U. (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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アイテムのパーマリンク: https://hdl.handle.net/21.11116/0000-0000-CE88-F 版のパーマリンク: https://hdl.handle.net/21.11116/0000-0002-5988-1

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Ehmke, N., 著者
Graul-Neumann, L., 著者
Smorag, L., 著者
Koenig, R., 著者
Segebrecht, L., 著者
Magoulas, P., 著者
Scaglia, F., 著者
Kilic, E., 著者
Hennig, A. F., 著者
Adolphs, N., 著者
Saha, N., 著者
Fauler, B.¹, 著者
Kalscheuer, V. M.², 著者
Hennig, F.², 著者
Altmüller, J., 著者
Netzer, C., 著者
Thiele, H., 著者
Nürnberg, P., 著者
Yigit, G., 著者
Jäger, M., 著者
Hecht, J., 著者Krüger, U., 著者Mielke, T., 著者Krawitz, P. M., 著者Horn, D., 著者Schuelke, M., 著者Mundlos, S.³, 著者         Bacino, C. A., 著者Bonnen, P. E., 著者Wollnik, B., 著者Fischer-Zirnsak, B., 著者Kornak, U.³, 著者          全て表示

所属:
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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キーワード: 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

要旨: 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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言語: eng - English

日付: 出版: 2017-11-02

出版の状態: 出版

ページ: 11

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識別子（DOI, ISBNなど）: DOI: 10.1016/j.ajhg.2017.09.016
ISSN: 1537-6605 (Electronic)0002-9297 (Print)

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出版物名: The American Journal of Human Genetics

その他 : Am. J. Hum. Genet.

種別: 学術雑誌

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出版社, 出版地: American Society of Human Genetics

ページ: - 巻号: 101 (5) 通巻号: - 開始・終了ページ: 833 - 843 識別子（ISBN, ISSN, DOIなど）: ISSN: 0002-9297
CoNE: https://pure.mpg.de/cone/journals/resource/954925377893_1

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