NAA15-related genetic disorders are caused by changes in the NAA15 gene. The NAA15 gene is thought to be important in the development and function of the brain and other organs. N-alpha-acetylation is one of the most common co-translational protein modifications in humans and is essential for normal cell function. NAA15 encodes for the binding protein NAA15, which is a subunit in the N-terminal acetyltransferase A (NatA) complex, which also includes NAA10. A regulatory subunit of the NatA complex is the Huntington-interacting protein (HYPK).
Biochemical analyses of variants as part of the human NatA complex, as well as enzymatic analyses with and without the HYPK regulatory subunit, help to explain some of the phenotypic differences seen among the different variants. This is a very rare condition, with only several dozen families identified worldwide. Many of the variants involving NAA15 are truncating variants, which prematurely terminate the protein, thus leading to the expression usually of either a smaller truncated protein or to no protein at all from that allele, due to nonsense-mediated decay of the messenger RNA. However, given that these mutations occur in heterozygous fashion, that means that the level of normal protein may still be at ~50% of the normal levels, which can explain the quite variable expression of phenotypic traits. Future research with cell lines and mouse models might be able to help explain the widely variable nature of the phenotype.