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

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, 50(10), 1442-1451. doi:10.1038/s41588-018-0220-y.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0002-4F34-C Version Permalink: http://hdl.handle.net/21.11116/0000-0002-4F35-B
Genre: Journal Article

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Basilicata, M. Felicia , Author
Bruel, Ange-Line , Author
Semplicio, Giuseppe , Author
Keller Valsecchi, Claudia Isabelle , Author
Aktaş, Tuğçe , Author
Duffourd, Yannis , Author
Rumpf, Tobias, Author
Morton, Jenny , Author
Bache, Iben, Author
Szymanski, Witold G. , Author
Gilissen, Christian , Author
Vanakker, Olivier , Author
Õunap, Katrin , Author
Mittler, Gerhard, Author
van der Burgt, Ineke , Author
El Chehadeh, Salima , Author
Cho, Megan T., Author
Pfundt, Rolph , Author
Tan, Tiong Yang , Author
Kirchhoff, Maria, Author
Menten, Björn , AuthorVergult, Sarah , AuthorLindstrom, Kristin , AuthorReis, André, AuthorJohnson, Diana S., AuthorFryer, Alan, AuthorMcKay, Victoria , AuthorStudy, D D D, AuthorFisher, Richard B. , AuthorThauvin-Robinet, Christel , AuthorFrancis, David, AuthorRoscioli, Tony, AuthorPajusalu, Sander , AuthorRadtke, Kelly, AuthorGanesh, Jaya , AuthorBrunner, Han G., AuthorWilson, Meredith , AuthorFaivre, Laurence , AuthorKalscheuer, Vera M.1, Author              Thevenon, Julien , AuthorAkhtar, Asifa , Author more..
Affiliations:
1Chromosome Rearrangements and Disease (Vera Kalscheuer), Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2385702              

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 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.

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Language(s): eng - English
 Dates: 2018-09-172018-10
 Publication Status: Published in print
 Pages: -
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 Rev. Method: -
 Identifiers: DOI: 10.1038/s41588-018-0220-y
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Title: Nature Genetics
  Other : Nature Genet.
Source Genre: Journal
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Publ. Info: New York, NY : Nature America, Inc.
Pages: 10 Volume / Issue: 50 (10) Sequence Number: - Start / End Page: 1442 - 1451 Identifier: ISSN: 1061-4036
CoNE: https://pure.mpg.de/cone/journals/resource/954925598609