A nonsense variant in the N-terminal acetyltransferase NAA30 may be associated with global developmental delay and tracheal cleft.
N-terminal acetylation
N-terminal acetyltransferase
NAA30
NatC
autism spectrum disorder
global developmental delay
Journal
American journal of medical genetics. Part A
ISSN: 1552-4833
Titre abrégé: Am J Med Genet A
Pays: United States
ID NLM: 101235741
Informations de publication
Date de publication:
09 2023
09 2023
Historique:
revised:
03
06
2023
received:
02
04
2023
accepted:
13
06
2023
medline:
21
8
2023
pubmed:
30
6
2023
entrez:
30
6
2023
Statut:
ppublish
Résumé
Most human proteins are N-terminally acetylated by N-terminal acetyltransferases (NATs), which play crucial roles in many cellular functions. The NatC complex, comprising the catalytic subunit NAA30 and the auxiliary subunits NAA35 and NAA38, is estimated to acetylate up to 20% of the human proteome in a co-translational manner. Several NAT enzymes have been linked to rare genetic diseases, causing developmental delay, intellectual disability, and heart disease. Here, we report a de novo heterozygous NAA30 nonsense variant c.244C>T (p.Q82*) (NM_001011713.2), which was identified by whole exome sequencing in a 5-year-old boy presenting with global development delay, autism spectrum disorder, hypotonia, tracheal cleft, and recurrent respiratory infections. Biochemical studies were performed to assess the functional impact of the premature stop codon on NAA30's catalytic activity. We find that NAA30-Q82* completely disrupts the N-terminal acetyltransferase activity toward a classical NatC substrate using an in vitro acetylation assay. This finding corresponds with structural modeling showing that the truncated NAA30 variant lacks the entire GNAT domain, which is required for catalytic activity. This study suggests that defective NatC-mediated N-terminal acetylation can cause disease, thus expanding the spectrum of NAT variants linked to genetic disease.
Identifiants
pubmed: 37387332
doi: 10.1002/ajmg.a.63338
doi:
Substances chimiques
N-Terminal Acetyltransferases
EC 2.3.1.88
NAA30 protein, human
EC 2.3.1.256
N-Terminal Acetyltransferase C
EC 2.3.1.256
Types de publication
Case Reports
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2402-2410Informations de copyright
© 2023 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.
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