The NAA10-related neurodevelopmental syndrome: proteomic insights from patient-derived neuronal iPSCs

A family of Nα-terminal acetyltransferase (NAT) complexes is responsible for the mainly co-translational acetylation of the nascent protein N-termini of ~80% of the human proteome. Although the functional implications of this modification remain elusive, a role in protein folding and stability has been suggested. Mutations in the catalytic subunit NAA10 of the Nα-terminal acetyltransferase A (NatA) complex give rise to series of rare X-linked developmental disorders collectively termed the NAA10-related neurodevelopmental syndrome. The symptoms observed in the predominantly male patients vary from mild to very severe mental and physical disabilities. Patient-derived induced pluripotent stem cells (iPSCs) harboring the NAA10 R83C mutation were generated, and have consequenty been re-differentiated into GABAergic neurons. The R83C mutation deactivates the acetyl CoA-binding pocket and renders the NatA complex catalytically inactive. We characterized the proteome and N-terminal acetylome of these neuronal cell lines with disturbed NatA activity and gained fundamental insights in the disease mechanisms of this particular NAA10-related neurodevelopmental syndrome.