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

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

  • Genet Med. 2021 Nov;23(11):2213-2218. doi: 10.1038/s41436-021-01264-0.
Jennifer Morrison # 1,  Norah K Altuwaijri # 2,  Kirsten Brønstad # 3,  Henriette Aksnes # 3,  Hessa S Alsaif 2,  Anthony Evans 4,  Mais Hashem 2,  Patricia G Wheeler 1,  Bryn D Webb # 4,  Fowzan S Alkuraya # 2,  Thomas Arnesen # 5 6 7
Affiliations

Affiliations

  • 1 Division of Genetics, Arnold Palmer Hospital, Orlando, FL, USA.
  • 2 Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
  • 3 Department of Biomedicine, University of Bergen, Bergen, Norway.
  • 4 Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 5 Department of Biomedicine, University of Bergen, Bergen, Norway. thomas.arnesen@uib.no.
  • 6 Department of Biological Sciences, University of Bergen, Bergen, Norway. thomas.arnesen@uib.no.
  • 7 Department of Surgery, Haukeland University Hospital, Bergen, Norway. thomas.arnesen@uib.no.
  • # Contributed equally.
PMID: 34230638 DOI: 10.1038/s41436-021-01264-0
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.

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