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

M Felicia Basilicata 1 Ange-Line Bruel 2, 3, 4, 5 Giuseppe Semplicio 1 Claudia Isabelle Keller Valsecchi 1 Tuğçe Aktaş 1 Yannis Duffourd 2, 3, 4, 5 Tobias Rumpf 1 Jenny Morton 6, 7 Iben Bache 8 Witold Szymanski 1 Christian Gilissen 9 Olivier Vanakker 10 Katrin Ounap Gerhard Mittler 1 Ineke van Der Burgt 11 Salima El Chehadeh 2, 3, 4 Megan T Cho 12 Rolph Pfundt 11, 9 Tiong Yang Tan 13 Maria Kirchhoff 14 Björn Menten 15 Sarah Vergult 15 Kristin Lindstrom André Reis 16, 17 Diana Johnson 18 Alan Fryer 19 Victoria Mckay 19 - Ddd Study Richard Fisher Christel Thauvin-Robinet 2, 3, 4, 5 David Francis Tony Roscioli Sander Pajusalu Kelly Radtke Jaya Ganesh Han Brunner Meredith Wilson Laurence Faivre 2, 3, 4, 5 Vera M. Kalscheuer Julien Thevenon 2, 3, 4, 5, 20, * Asifa Akhtar 1, * 
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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Soumis le : mercredi 6 mars 2019 - 09:57:09
Dernière modification le : vendredi 20 mai 2022 - 09:06:40

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M Felicia Basilicata, Ange-Line Bruel, Giuseppe Semplicio, Claudia Isabelle Keller Valsecchi, Tuğçe Aktaş, et al.. De novo mutations in MSL3 cause an X-linked syndrome marked by impaired histone H4 lysine 16 acetylation. Nature Genetics, 2018, 50 (10), pp.1442-1451. ⟨10.1038/s41588-018-0220-y⟩. ⟨hal-02058702⟩



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