Phenotypic and biochemical analysis of an international cohort of individuals with variants in NAA10 and NAA15

Abstract

N-alpha-acetylation is one of the most common co-translational protein modifications in humans and is essential for normal cell function. NAA10 encodes for the enzyme NAA10, which is the catalytic subunit in the N-terminal acetyltransferase A (NatA) complex. The auxiliary and regulatory subunits of the NatA complex are NAA15 and Huntington-interacting protein (HYPK), respectively. Through a genotype-first approach with exome sequencing, we identified and phenotypically characterized 30 individuals from 30 unrelated families with 17 different de novo or inherited, dominantly acting missense variants in NAA10 or NAA15. Clinical features of affected individuals include variable levels of intellectual disability, delayed speech and motor milestones and autism spectrum disorder. Additionally, some subjects present with mild craniofacial dysmorphology, congenital cardiac anomalies and seizures. One of the individuals is an 11-year-old boy with a frameshift variant in exon 7 of NAA10, who presents most notably with microphthalmia, which confirms a prior finding with a single family with Lenz microphthalmia syndrome. 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.

Molecular Basis for N-terminal Alpha-Synuclein Acetylation by Human NatB

“…S4A). Recent reports have described the role of the small molecule IP6 (inositol hexakisphosphate) in hNatA activity, where it is found to act as "glue" between the C-terminal and core domains in hNAA15 and hNAA10 via a series of hydrogen bonds and electrostatic interactions [35,68]. While no corresponding small molecules have been identified to play a similar role in hNatB, our model shows that this interaction is replaced by an extended loop that connects the a31 helix with the a32 helix of hNatB-NAA25.…”

A Japanese boy with NAA10-related syndrome and hypertrophic cardiomyopathy

“…The frequently observed symptoms are as follows: Ree et al 10 Popp et al 6 Esmailpour et al 5 Cheng et al 2 Slavotinek and Lee 11 , Johnston et al 7 Johnston et al 7 Johnston et al 7 The present case ID, motor developmental delay, growth failure, ophthalmic diseases, skeletal disorders, including scoliosis or digital anomalies, and cardiac disorders. Most NAA10 mutation types in male patients are missense variants, but three families, including the present case, harbor truncated mutations 2,7 . Patients with NAA10 mutations in further unstructured domains (exons 7 or 8) tend to exhibit microphthalmia or anophthalmia (Fig.…”

Molecular basis for N-terminal acetylation by human NatE and its modulation by HYPK

“…In prior studies, we reported that a hNAA15-T406Y mutant can disassociate hNAA50 from hNatA in vitro 46 , while a hNAA15-L814P mutant is defective for HYPK inhibition and reduces hNatA thermostability 37 . Based on these observations, we also carried out a MS analysis of the V5 immunoprecipitates of the hNAA15-T406Y-V5 and hNAA15-L814P-V5 mutants to evaluate the effect of the mutation's on formation of the hNatE/HYPK tetrameric complex (Supplementary Data 1).…”

“…About one-half of the human N-terminal acetylome is mediated by hNatA. Mutations in either the hNAA10 catalytic or hNAA15 auxiliary subunits have been correlated with a broad spectrum of pathologies, including intellectual disabilities, developmental delay, autism spectrum disorders, craniofacial dysmorphology, congenital cardiac anomalies, and Ogden syndrome [30][31][32][33][34][35][36][37][38][39] . Aberrant NatA activity has also been correlated with neurodegenerative disorders and cancer although a causative role of NatA is less clear 40 .…”