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

Nadja Ehmke; Luitgard Graul-Neumann; Lukasz Smorag; Rainer Koenig; Lara Segebrecht; Pilar Magoulas; Fernando Scaglia; Esra Kilic; Anna F Hennig; Nicolai Adolphs; Namrata Saha; Beatrix Fauler; Vera M Kalscheuer; Friederike Hennig; Janine Altmüller; Christian Netzer; Holger Thiele; Peter Nürnberg; Gökhan Yigit; Marten Jäger; Jochen Hecht; Ulrike Krüger; Thorsten Mielke; Peter M Krawitz; Denise Horn; Markus Schuelke; Stefan Mundlos; Carlos A Bacino; Penelope E Bonnen; Bernd Wollnik; Björn Fischer-Zirnsak; Uwe Kornak

doi:10.1016/j.ajhg.2017.09.016

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.

Authors

Nadja Ehmke¹, Luitgard Graul-Neumann², Lukasz Smorag³, Rainer Koenig⁴, Lara Segebrecht², Pilar Magoulas⁵, Fernando Scaglia⁵, Esra Kilic⁶, Anna F Hennig⁷, Nicolai Adolphs⁸, Namrata Saha⁹, Beatrix Fauler¹⁰, Vera M Kalscheuer¹¹, Friederike Hennig¹¹, Janine Altmüller¹², Christian Netzer¹³, Holger Thiele¹⁴, Peter Nürnberg¹⁵, Gökhan Yigit³, Marten Jäger¹⁶, Jochen Hecht¹⁷, Ulrike Krüger¹⁶, Thorsten Mielke¹⁰, Peter M Krawitz¹⁸, Denise Horn², Markus Schuelke¹⁹, Stefan Mundlos¹⁸, Carlos A Bacino⁵, Penelope E Bonnen²⁰, Bernd Wollnik³, Björn Fischer-Zirnsak¹⁸, Uwe Kornak²¹

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].

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/P_i 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.

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

MeSH terms

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
Growth Disorders
Humans
Hydrogen Peroxide / pharmacology
Hypertrichosis / genetics*
Infant
Membrane Potential, Mitochondrial / drug effects
Membrane Potential, Mitochondrial / genetics
Mitochondria / drug effects
Mitochondria / genetics*
Mitochondrial Proteins / genetics*
Mutation / genetics*
Oxidative Stress / genetics
Progeria / genetics

Substances

ATP-Mg-Pi carrier proteins, mitochondria
Antiporters
Calcium-Binding Proteins
DNA, Mitochondrial
Mitochondrial Proteins
SLC25A24 protein, human
Adenosine Triphosphate
Hydrogen Peroxide

Supplementary concepts

Progeroid Syndrome, Congenital, Petty Type
Progeroid syndrome, neonatal

Grants and funding

R01 NS083726/NS/NINDS NIH HHS/United States