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

  • Am J Hum Genet. 2017 Nov 2;101(5):833-843. doi: 10.1016/j.ajhg.2017.09.016.
Nadja Ehmke  1 ,  Luitgard Graul-Neumann  2 ,  Lukasz Smorag  3 ,  Rainer Koenig  4 ,  Lara Segebrecht  2 ,  Pilar Magoulas  5 ,  Fernando Scaglia  5 ,  Esra Kilic  6 ,  Anna F Hennig  7 ,  Nicolai Adolphs  8 ,  Namrata Saha  9 ,  Beatrix Fauler  10 ,  Vera M Kalscheuer  11 ,  Friederike Hennig  11 ,  Janine Altmüller  12 ,  Christian Netzer  13 ,  Holger Thiele  14 ,  Peter Nürnberg  15 ,  Gökhan Yigit  3 ,  Marten Jäger  16 ,  Jochen Hecht  17 ,  Ulrike Krüger  16 ,  Thorsten Mielke  10 ,  Peter M Krawitz  18 ,  Denise Horn  2 ,  Markus Schuelke  19 ,  Stefan Mundlos  18 ,  Carlos A Bacino  5 ,  Penelope E Bonnen  20 ,  Bernd Wollnik  3 ,  Björn Fischer-Zirnsak  18 ,  Uwe Kornak  21
Affiliations
  • 1. Institute of Medical and Human Genetics, Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany; Berlin Institute of Health, 10117 Berlin, Germany; Max Planck Institute for Molecular Genetics, Development and Disease Group, 14195 Berlin, Germany. Electronic address: [email protected].
  • 2. Institute of Medical and Human Genetics, Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany.
  • 3. Institut für Humangenetik, Universitätsmedizin Göttingen, 37073 Göttingen, Germany.
  • 4. Institute of Human Genetics, Goethe University Frankfurt, 60590 Frankfurt am Main, Germany.
  • 5. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.
  • 6. Pediatric Genetics, Pediatric Hematology Oncology Research &Training Hospital, 06110 Ankara, Turkey.
  • 7. Institute of Medical and Human Genetics, Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany; Berlin-Brandenburg Center for Regenerative Therapies, Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany.
  • 8. Department of Craniomaxillofacial Surgery, Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany.
  • 9. Institute of Medical and Human Genetics, Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany; Max Planck Institute for Molecular Genetics, Development and Disease Group, 14195 Berlin, Germany; Berlin-Brandenburg School for Regenerative Therapies, Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany; Max Planck International Research Network on Aging, 18057 Rostock, Germany.
  • 10. Max Planck Institute for Molecular Genetics, Microscopy and Cryo-electron Microscopy Group, 14195 Berlin, Germany.
  • 11. Max Planck Institute for Molecular Genetics, Development and Disease Group, 14195 Berlin, Germany.
  • 12. Cologne Center for Genomics, University of Cologne, 50931 Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany.
  • 13. Institute of Human Genetics, University Hospital Cologne, 50931 Cologne, Germany.
  • 14. Cologne Center for Genomics, University of Cologne, 50931 Cologne, Germany.
  • 15. Cologne Center for Genomics, University of Cologne, 50931 Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, 50931 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, 50674 Cologne, Germany.
  • 16. Genomics Core Facility, Campus Virchow Klinikum, Berlin Institute of Health, 13353 Berlin, Germany.
  • 17. Center for Genomic Regulation, Barcelona Institute for Science and Technology, Dr. Aiguader 88, 08003 Barcelona, Spain; Universitat Pompeu Fabra, 08002 Barcelona, Spain.
  • 18. Institute of Medical and Human Genetics, Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany; Max Planck Institute for Molecular Genetics, Development and Disease Group, 14195 Berlin, Germany; Berlin-Brandenburg Center for Regenerative Therapies, Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany.
  • 19. Department of Neuropediatrics and NeuroCure Clinical Research Center, Charité - Universitätsmedizin Berlin, 10117 Berlin, Germany.
  • 20. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
  • 21. Institute of Medical and Human Genetics, Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany; Max Planck Institute for Molecular Genetics, Development and Disease Group, 14195 Berlin, Germany; Berlin-Brandenburg Center for Regenerative Therapies, Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany. Electronic address: [email protected].
PMID: 29100093 DOI: 10.1016/j.ajhg.2017.09.016
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.

Keywords
Gorlin-Chaudhry-Moss syndrome; SLC25A24; craniosynostosis; cutis laxa; hypertrichosis; lipoatrophy; mitochondrial swelling; oxidative stress; premature aging.