De novo mutations in MSL3 cause an X-linked syndrome marked by impaired histone H4 lysine 16 acetylation PMID: 30224647

ADC Targets in Oncology

2026-04-10

De novo mutations in MSL3 cause an X-linked syndrome marked by impaired histone H4 lysine 16 acetylation

Nat Genet. 2018 Oct;50(10):1442-1451. doi: 10.1038/s41588-018-0220-y.

M Felicia Basilicata ¹ , Ange-Line Bruel ² , Giuseppe Semplicio ¹ , Claudia Isabelle Keller Valsecchi ¹ , Tuğçe Aktaş ¹ , Yannis Duffourd ² , Tobias Rumpf ¹ , Jenny Morton ³ , Iben Bache ⁴ ⁵ , Witold G Szymanski ¹ , Christian Gilissen ⁶ , Olivier Vanakker ⁷ , Katrin Õunap ⁸ , Gerhard Mittler ¹ , Ineke van der Burgt ⁶ , Salima El Chehadeh ² ⁹ , Megan T Cho ¹⁰ , Rolph Pfundt ⁶ , Tiong Yang Tan ¹¹ , Maria Kirchhoff ⁴ , Björn Menten ⁷ , Sarah Vergult ⁷ , Kristin Lindstrom ¹² , André Reis ¹³ , Diana S Johnson ¹⁴ , Alan Fryer ¹⁵ , Victoria McKay ¹⁵ , DDD Study , Richard B Fisher ¹⁶ , Christel Thauvin-Robinet ² , David Francis ¹⁷ , Tony Roscioli ¹⁸ ¹⁹ ²⁰ , Sander Pajusalu ⁸ , Kelly Radtke ²¹ , Jaya Ganesh ²² , Han G Brunner ⁶ ²³ , Meredith Wilson ²⁴ , Laurence Faivre ² , Vera M Kalscheuer ²⁵ , Julien Thevenon ²⁶ ²⁷ , Asifa Akhtar ²⁸

Affiliations

1. Max Planck Institute of Immunobiology and Epigenetics, Freiburg im Breisgau, Germany.
2. Inserm UMR 1231 GAD, Genetics of Developmental disorders and Centre de Référence Maladies Rares Anomalies du Développement et syndromes malformatifs FHU TRANSLAD, Université de Bourgogne-Franche Comté, Dijon, France.
3. West Midlands Regional Clinical Genetics Service and Birmingham Health Partners, Birmingham Women's Hospital NHS Foundation Trust, Birmingham, UK.
4. Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
5. Wilhelm Johannsen Centre for Functional Genome Research, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark.
6. Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands.
7. Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
8. Department of Clinical Genetics, United Laboratories, Tartu University Hospital and Institute of Clinical Medicine, University of Tartu, Tartu, Estonia.
9. Service de Génétique Médicale, Hôpital de Hautepierre, Strasbourg, France.
10. GeneDx, Gaithersburg, MD, USA.
11. Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Royal Children's Hospital, University of Melbourne Department of Paediatrics, Parkville, VIC, Australia.
12. Division of Genetics and Metabolism, Phoenix Children's Hospital, Phoenix, AZ, USA.
13. Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
14. Sheffield Clinical Genetics Service, Sheffield Children's NHS Foundation Trust, Sheffield, UK.
15. Department of Clinical Genetics, Liverpool Women's NHS Foundation Trust, Liverpool, UK.
16. Northern Genetics Service, Teesside Genetics Unit, The James Cook University Hospital, Middlesbrough, UK.
17. Cytogenetic Laboratory, Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Victoria, Australia.
18. Neuroscience Research Australia, Sydney, New South Wales, Australia.
19. Prince of Wales Clinical School, University of New South Wales, Sydney, New South Wales, Australia.
20. Department of Medical Genetics, Sydney Children's Hospital, Sydney, New South Wales, Australia.
21. Department of Clinical Genomics, Ambry Genetics, Aliso Viejo, CA, USA.
22. Division of Genetics, Cooper University Hospital and Cooper Medical School at Rowan University, Camden, NJ, USA.
23. Department of Clinical Genetics and School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands.
24. Department of Clinical Genetics, Children's Hospital at Westmead, Disciplines of Genetic Medicine and Child and Adolescent Health, University of Sydney, Sydney, New South Wales, Australia.
25. Research Group Development and Disease, Max Planck Institute for Molecular Genetics, Berlin, Germany.
26. Inserm UMR 1231 GAD, Genetics of Developmental disorders and Centre de Référence Maladies Rares Anomalies du Développement et syndromes malformatifs FHU TRANSLAD, Université de Bourgogne-Franche Comté, Dijon, France. [email protected].
27. CNRS UMR 5309, INSERM, U1209, Institute of Advanced Biosciences, Université Grenoble-Alpes CHU Grenoble, Grenoble, France. [email protected].
28. Max Planck Institute of Immunobiology and Epigenetics, Freiburg im Breisgau, Germany. [email protected].

Abstract

The etiological spectrum of ultra-rare developmental disorders remains to be fully defined. Chromatin regulatory mechanisms maintain cellular identity and function, where misregulation may lead to developmental defects. Here, we report pathogenic variations in MSL3, which encodes a member of the chromatin-associated male-specific lethal (MSL) complex responsible for bulk histone H4 lysine 16 acetylation (H4K16ac) in flies and mammals. These variants cause an X-linked syndrome affecting both sexes. Clinical features of the syndrome include global developmental delay, progressive gait disturbance, and recognizable facial dysmorphism. MSL3 mutations affect MSL complex assembly and activity, accompanied by a pronounced loss of H4K16ac levels in vivo. Patient-derived cells display global transcriptome alterations of pathways involved in morphogenesis and cell migration. Finally, we use histone deacetylase inhibitors to rebalance acetylation levels, alleviating some of the molecular and cellular phenotypes of patient cells. Taken together, we characterize a syndrome that allowed us to decipher the developmental importance of MSL3 in humans.