Missense NAA20 variants impairing the NatB protein N-terminal acetyltransferase cause autosomal recessive developmental delay, intellectual disability, and microcephaly.
2021
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. 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. 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. 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.
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