MSL (male specific lethal) factors commonly act in a protein complex to regulate chromatin-associated gene transcription. MSL3, one of these factors, is responsible for incorporation of MOF, a histone acetyle transferase and a key protein of the MSL complex, which effects specific epigenetic histone modifications (H4K16ac). While MSL3 function in dosage compensation of X-linked genes in flies has been known for some time, its precise role in human development has still been unclear. Scientists have now identified in 16 children de novo mutations in the X-linked MSL3 gene as causing a rare, distinctive syndrome. The complex phenotype includes developmental delay, facial dysmorphism and a progressive neurological disorder. The mutations were found both in male patients (hemizygous) and in female patients (heterozygous) who presented with a similar clinical manifestation.

In further functional experiments performed on patient fibroblasts, the researchers discovered that the newly identified mutations lead to a loss of MSL3 function and a markedly reduced number of H4K16ac modifications and, thereby, result in a misregulation of developmental pathways. Additionally, their investigations showed that treatment of the patient cells with histone deacetylase inhibitors alleviated cellular and molecular phenotypes. This result may potentially open up new ways for the development of a therapy for these patients.

The results of this study have been published in Nature Genetics.

Basilicata MF, Bruel AL, Semplicio G, […] Akhtar A. De novo mutations in MSL3 cause an X-linked syndrome marked by impaired histone H4 lysine 16 acetylation. Nat Genet. 2018 Sep 17. doi: 10.1038/s41588-018-0220-y. [Epub ahead of print]