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

Journal article

Publication Details

Author(s): 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
Journal: Nature Genetics
Publication year: 2018
Volume: 50
Journal issue: 10
Pages range: 1442-1451
ISSN: 1061-4036


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.

External institutions with authors

Ambry Genetics
Birmingham Women's NHS Foundation Trust
Copenhagen University Hospital
James Cook University Hospital
Liverpool Women's NHS Foundation Trust
Max-Planck-Institut für Immunbiologie und Epigenetik (MPI-IE) / Max Planck Institute of Immunobiology and Epigenetics
Max-Planck-Institut für molekulare Genetik / Max Planck Institute for Molecular Genetics
Neuroscience Research Australia NeuRA
Phoenix Children's Hospital
Radboud University Nijmegen
Rowan University
Royal Children's Hospital Parkville
Sheffield Children's NHS Foundation Trust
The University of Melbourne
Université Bourgogne Franche-Comté
University Hospital Ghent
University of Sydney
University of Tartu

How to cite

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.

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.


Last updated on 2018-03-12 at 20:08