Biochemical analysis of novel NAA10 variants suggests distinct pathogenic mechanisms involving impaired protein N-terminal acetylation

Nina Mctiernan,Anna S Bjørheim,Marie F Smeland,Lisbeth Tranebjærg,Berkley Schmidt,Melissa M Boerrigter,Zeynep Tümer,Maja L Nybo,Thomas Arnesen,Jacob S Hogue,William G Wilson

doi:10.1007/s00439-021-02427-4

Abstract

NAA10 is the catalytic subunit of the N-terminal acetyltransferase complex, NatA, which is responsible for N-terminal acetylation of nearly half the human proteome. Since 2011, at least 21 different NAA10 missense variants have been reported as pathogenic in humans. The clinical features associated with this X-linked condition vary, but commonly described features include developmental delay, intellectual disability, cardiac anomalies, brain abnormalities, facial dysmorphism and/or visual impairment. Here, we present eight individuals from five families with five different de novo or inherited NAA10 variants. In order to determine their pathogenicity, we have performed biochemical characterisation of the four novel variants c.16G>C p.(A6P), c.235C>T p.(R79C), c.386A>C p.(Q129P) and c.469G>A p.(E157K). Additionally, we clinically describe one new case with a previously identified pathogenic variant, c.384T>G p.(F128L). Our study provides important insight into how different NAA10 missense variants impact distinct biochemical functions of NAA10 involving the ability of NAA10 to perform N-terminal acetylation. These investigations may partially explain the phenotypic variability in affected individuals and emphasise the complexity of the cellular pathways downstream of NAA10.

Highlights

N-terminal acetylation (Nt-Ac) is a widespread protein modification that contributes to a greatly diversified proteome, as approximately 80–90% of human proteins are subjected to acetylation at their N-terminus (Aksnes et al 2019; Arnesen et al 2009)
NatA co-translationally transfers an acetyl group from acetyl coenzyme A (Ac-CoA) to N-termini starting with serine, valine, cysteine, glycine, alanine, or threonine, and this group of N-termini encompasses nearly half the human proteome (Arnesen et al 2009)
We have carried out biochemical characterisation of four novel NAA10 missense variants [p.(A6P), p.(R79C), p.(Q129P) and p.(E157K)] to evaluate their pathogenicity, and clinically described one new individual

Summary

Introduction

N-terminal acetylation (Nt-Ac) is a widespread protein modification that contributes to a greatly diversified proteome, as approximately 80–90% of human proteins are subjected to acetylation at their N-terminus (Aksnes et al 2019; Arnesen et al 2009). Seven N-terminal acetyltransferases (NATs) have been identified in humans, named NatA-NatF and NatH, all of which have distinct substrate specificities (Aksnes et al 2019). NatA co-translationally transfers an acetyl group from acetyl coenzyme A (Ac-CoA) to N-termini starting with serine, valine, cysteine, glycine, alanine, or threonine, and this group of N-termini encompasses nearly half the human proteome (Arnesen et al 2009). In addition to NAA10’s role as the catalytic subunit of NatA, a cellular population of NAA10 exists as monomers and is proposed to exert different biochemical functions (Arnesen et al 2005; Damme et al 2011). NAA10 influences gene transcription through non-catalytic regulation of DNMT1 (Lee et al 2010, 2017)

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Conclusion