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

MPS-Authors

Basilicata,  M. Felicia
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Semplicio,  Giuseppe
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Keller Valsecchi,  Claudia Isabelle
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Aktaş,  Tuğçe
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Rumpf,  Tobias
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Szymanski,  Witold G.
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Mittler,  Gerhard
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Akhtar,  Asifa
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Citation

Basilicata, M. F., Bruel, A.-L., Semplicio, G., Keller Valsecchi, C. I., Aktaş, T., Duffourd, Y., et al. (2018). De novo mutations in MSL3 cause an X-linked syndrome marked by impaired histone H4 lysine 16 acetylation. Nature Genetics, 1442-1451. doi:10.1038/s41588-018-0220-y.


Cite as: http://hdl.handle.net/21.11116/0000-0002-C24D-D
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.