TRRAP is composed of 3859 amino acids. It is part of a multi-protein assembly that is essential to the activity and localization of most histone acetyltransferases (HATs). In fact, TRAPP recruit HATs to chromatin. HATs are major activator of the transcription process by acetylation of histone tails, thus playing a major role in regulation of eukaryotic gene expression. It has been suggested that TRRAP plays an important role in cell-cycle regulation, self-renewal and correction of differentiation. Pathogenic effects of TRRAP variants may be due to dysregulation of acetylation. This process has been associated with severe neurodevelopmental disorders. The expression of several genes implicated in neuronal function and ion transport is affected by TRRAP mutations. TRRAP is evolutionarily conserved and is among the top five genes intolerant to missense variation. Research shows that missense variants act either as gain-of-function or dominant-negative variants. Haploinsufficiency of TRRAP is likely to be prenatally lethal. 17 distinct de novo or apparently de novo variants were identified in TRRAP in 24 individuals. 13 variants between codons 1031 and 1159 formed a cluster with individuals showing phenotypes related to the first clinical spectra. Developmental signaling pathways in embryologic development are probably disrupted by variants falling in the 1031-1159 region, which would explain the multiple malformations of affected individuals.
TRRAP