Missense NAA20 variantsimpairing the NatB protein N-terminal acetyltransferase cause autosomal recessivedevelopmental delay, intellectual disability, and microcephaly

Abstract

Purpose N-terminal acetyltransferases modify proteins by adding an acetyl moiety to the first amino acid and are vital for protein and cell function. The NatB complex acetylates 20% of the human proteome and is composed of the catalytic subunit NAA20 and the auxiliary subunit NAA25. In five individuals with overlapping phenotypes, we identified recessive homozygous missense variants in NAA20. Methods Two different NAA20 variants were identified in affected individuals in two consanguineous families by exome and genome sequencing. Biochemical studies were employed to assess the impact of the NAA20 variants on NatB complex formation and catalytic activity. Results Two homozygous variants, NAA20 p.Met54Val and p.Ala80Val (GenBank: NM_016100.4, c.160A>G and c.239C>T), segregated with affected individuals in two unrelated families presenting with developmental delay, intellectual disability, and microcephaly. Both NAA20-M54V and NAA20-A80V were impaired in their capacity to form a NatB complex with NAA25, and in vitro acetylation assays revealed reduced catalytic activities toward different NatB substrates. Thus, both NAA20 variants are impaired in their ability to perform cellular NatB-mediated N-terminal acetylation. Conclusion We present here a report of pathogenic NAA20 variants causing human disease and data supporting an essential role for NatB-mediated N-terminal acetylation in human development and physiology.

N-terminal acetylation shields proteins from degradation and promotes age-dependent motility and longevity

“…Nt-acetylation catalyzed by the NATs is one of the most common protein modifications in eukaryotes, whose general role remains enigmatic. Mutations in the NATs can cause rare disorders, resulting in developmental delay, intellectual disability, and congenital heart defects (Cheng et al, 2018; Morrison et al, 2021; Muffels et al, 2021; Rope et al, 2011; Ward et al, 2021). The molecular framework and consequently the mechanistic basis for how the NATs manifest in cellular and organismal phenotypes remains however largely unknown.…”

“…Given the prevalence of Nt-acetylation, NATs regulate a wide range of cellular processes, ranging from metabolism, cell proliferation and migration to differentiation and stress response (Aksnes et al, 2019). Dysregulation of Nt-acetylation can cause developmental disorders, by affecting brain and heart development, and contribute to cancer development (Aksnes et al, 2019; Cheng et al, 2018; Morrison et al, 2021; Muffels et al, 2021; Rope et al, 2011; Ward et al, 2021).…”

“…Dysregulation of Nt-acetylation can cause developmental disorders, by affecting brain and heart development, and contribute to cancer development (Aksnes et al, 2019;Cheng et al, 2018;Morrison et al, 2021;Muffels et al, 2021;Rope et al, 2011;Ward et al, 2021).…”

The dynamic architecture of Map1- and NatB-ribosome complexes coordinates the sequential modifications of nascent polypeptide chains

“…In yeast, it was shown that whereas N-α-acetylation by NatA seems to play a role in systemic adaptation control, modification by NatB seems rather to be important for protein folding [ 22 ]. Furthermore, depletion of NatB subunits to 30% of the wild-type level caused a 50% decrease in growth in Arabipopsis thaliana [ 23 ] and missense mutations in the catalytic domain NAA20 of human NatB were shown to cause autosomal recessive developmental delay, intellectual disability, and microcephaly, emphasizing the importance of NatB function for the cell [ 24 ].…”

Novel biallelic variants expand the phenotype of NAA20‐related syndrome

“…4,5 Pathogenic biallelic variants in NAA20 were associated with a human disease characterized by developmental delay (DD), intellectual disability (ID) and microcephaly. 6 To date, only five patients from two families carrying two different variants in NAA20 have been described with limited clinical details. 6 We report two Italian siblings harboring biallelic novel variant in NAA20 along with clinical data of the previously published families, expanding the phenotype of this neurodevelopmental disorder.…”