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

Basilicata MF, Bruel AL, Semplicio G, Valsecchi CIK, Aktas T, Duffourd Y, Rumpf T, Morton J, Bache I, Szymanski WG, Gilissen C, Vanakker O, Ounap K, Mittler G, Van Der Burgt I, El Chehadeh S, Cho MT, Pfundt R, Tan TY, Kirchhoff M, Menten B, Vergult S, Lindstrom K, Reis A, Johnson DS, Fryer A, Mckay V, Fisher RB, Thauvin-Robinet C, Francis D, Roscioli T, Pajusalu S, Radtke K, Ganesh J, Brunner HG, Wilson M, Faivre L, Kalscheuer VM, Thevenon J, Akhtar A (2018)

Publication Type: Journal article

Publication year: 2018

Journal

Book Volume: 50

Pages Range: 1442-1451

Journal Issue: 10

DOI: 10.1038/s41588-018-0220-y

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.

Authors with CRIS profile

Involved external institutions

Max-Planck-Institut für Immunbiologie und Epigenetik (MPI-IE) / Max Planck Institute of Immunobiology and Epigenetics Germany (DE) Université Bourgogne Franche-Comté France (FR) Birmingham Women's and Children's NHS Foundation Trust United Kingdom (GB) Copenhagen University Hospital Denmark (DK) Radboud University Nijmegen Netherlands (NL) University Hospital Ghent Belgium (BE) University of Tartu Estonia (EE) GeneDX United States (USA) (US) The University of Melbourne Australia (AU) Phoenix Children's Hospital United States (USA) (US) Sheffield Children's NHS Foundation Trust United Kingdom (GB) Liverpool Women's NHS Foundation Trust United Kingdom (GB) James Cook University Hospital United Kingdom (GB) Neuroscience Research Australia NeuRA Australia (AU) Ambry Genetics United States (USA) (US) University of Sydney (USYD) Australia (AU) Rowan University United States (USA) (US) Max-Planck-Institut für molekulare Genetik / Max Planck Institute for Molecular Genetics Germany (DE) Royal Children's Hospital Parkville Australia (AU)

How to cite

APA:

Basilicata, M.F., Bruel, A.-L., Semplicio, G., Valsecchi, C.I.K., Aktas, T., Duffourd, Y.,... Akhtar, A. (2018). De novo mutations in MSL3 cause an X-linked syndrome marked by impaired histone H4 lysine 16 acetylation. Nature Genetics, 50(10), 1442-1451. https://doi.org/10.1038/s41588-018-0220-y

MLA:

Basilicata, M. Felicia, et al. "De novo mutations in MSL3 cause an X-linked syndrome marked by impaired histone H4 lysine 16 acetylation." Nature Genetics 50.10 (2018): 1442-1451.

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