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)

1 MPI-IE - Max Planck Institute of Immunobiology and Epigenetics
2 Equipe GAD (LNC - U1231)
3 Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon)
4 FHU TRANSLAD (CHU de Dijon)
5 UBFC - Université Bourgogne Franche-Comté [COMUE]
6 West Midlands Regional Genetics Laboratory and Clinical Genetics Unit
7 Birmingham Women's Hospital
8 Copenhagen University Hospitals
9 Radboud University Medical Center [Nijmegen]
10 Center for Medical Genetics [Ghent]
11 Donders Institute for Brain, Cognition and Behaviour
12 GeneDx [Gaithersburg, MD, USA]
13 MCRI - Murdoch Children's Research Institute
14 Department of Clinical Genetics [Copenhagen]
15 Ghent University Hospital
16 Institute of Human Genetics [Erlangen, Allemagne]
17 FAU - Friedrich-Alexander Universität Erlangen-Nürnberg = University of Erlangen-Nuremberg
18 Department of Clinical Genetics (Sheffield Children’s NHS Foundation Trust)
19 Liverpool Women's NHS Foundation Trust
20 IAB - Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble)

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.

Mots clés: Ultra-rare developmental disorders; MSL3

Domaines: Génétique humaine

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⟩