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Missense NAA20 variants impairing the NatB protein N-terminal acetyltransferase cause autosomal recessive developmental delay, intellectual disability, and microcephaly
- Source :
- Genetics in Medicine
- Publication Year :
- 2021
- Publisher :
- Nature Publishing Group US, 2021.
-
Abstract
- 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.
- Subjects :
- 0301 basic medicine
Genetics
Microcephaly
NatB complex
Protein subunit
Biology
medicine.disease
Brief Communication
Phenotype
03 medical and health sciences
030104 developmental biology
0302 clinical medicine
Acetylation
Acetyltransferases
030220 oncology & carcinogenesis
Intellectual Disability
medicine
Human proteome project
Missense mutation
Humans
Exome
N-Terminal Acetyltransferase B
Genetics (clinical)
Subjects
Details
- Language :
- English
- ISSN :
- 15300366 and 10983600
- Volume :
- 23
- Issue :
- 11
- Database :
- OpenAIRE
- Journal :
- Genetics in Medicine
- Accession number :
- edsair.doi.dedup.....93d8fafc7c1012e0c66f06233c07e0da