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

(2018) NATURE GENETICS. 50(10). p.1442-1451
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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.
Keywords
DOSAGE COMPENSATION COMPLEX, INTELLECTUAL DISABILITY, PROTEIN INTERACTIONS, CELL-CYCLE, MOF, DEACETYLASE, DROSOPHILA, CHROMOSOME, CHROMATIN, ACETYLTRANSFERASE

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Chicago
Basilicata, M Felicia, Ange-Line Bruel, Giuseppe Semplicio, Claudia Isabelle Keller Valsecchi, Tuğçe Aktaş, Yannis Duffourd, Tobias Rumpf, 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.
APA
Basilicata, M. F., Bruel, A.-L., Semplicio, G., Valsecchi, C. I. K., Aktaş, T., Duffourd, Y., Rumpf, T., 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.
Vancouver
1.
Basilicata MF, Bruel A-L, Semplicio G, Valsecchi CIK, Aktaş T, Duffourd Y, 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):1442–51.
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. Print.
@article{8575609,
  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.},
  author       = {Basilicata, M Felicia and Bruel, Ange-Line and Semplicio, Giuseppe and Valsecchi, Claudia Isabelle Keller and Akta\c{s}, Tu\u{g}\c{c}e and Duffourd, Yannis and Rumpf, Tobias and Morton, Jenny and Bache, Iben and Szymanski, Witold G and Gilissen, Christian and Vanakker, Olivier and {\~O}unap, Katrin and Mittler, Gerhard and van der Burgt, Ineke and El Chehadeh, Salima and Cho, Megan T and Pfundt, Rolph and Tan, Tiong Yang and Kirchhoff, Maria and Menten, Bj{\"o}rn and Vergult, Sarah and Lindstrom, Kristin and Reis, Andr{\'e} and Johnson, Diana S and Fryer, Alan and McKay, Victoria and Fisher, Richard B and Thauvin-Robinet, Christel and Francis, David and Roscioli, Tony and Pajusalu, Sander and Radtke, Kelly and Ganesh, Jaya and Brunner, Han G and Wilson, Meredith and Faivre, Laurence and Kalscheuer, Vera M and Thevenon, Julien and Akhtar, Asifa},
  issn         = {1061-4036},
  journal      = {NATURE GENETICS},
  language     = {eng},
  number       = {10},
  pages        = {1442--1451},
  title        = {De novo mutations in MSL3 cause an X-linked syndrome marked by impaired histone H4 lysine 16 acetylation},
  url          = {http://dx.doi.org/10.1038/s41588-018-0220-y},
  volume       = {50},
  year         = {2018},
}

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