NAA10 p.(N101K) disrupts N-terminal acetyltransferase complex NatA and is associated with developmental delay and hemihypertrophy.
Acetylation
Amino Acid Sequence
Animals
Child, Preschool
Female
Genetic Predisposition to Disease
/ genetics
HeLa Cells
Humans
Intellectual Disability
/ genetics
Mice
Models, Molecular
Mutation
N-Terminal Acetyltransferase A
/ chemistry
N-Terminal Acetyltransferase E
/ chemistry
Phenotype
Protein Conformation
Proteus Syndrome
/ diagnostic imaging
Rats
Sequence Alignment
Yeasts
Zebrafish
Journal
European journal of human genetics : EJHG
ISSN: 1476-5438
Titre abrégé: Eur J Hum Genet
Pays: England
ID NLM: 9302235
Informations de publication
Date de publication:
02 2021
02 2021
Historique:
received:
20
11
2019
accepted:
08
09
2020
revised:
31
07
2020
pubmed:
26
9
2020
medline:
19
1
2022
entrez:
25
9
2020
Statut:
ppublish
Résumé
Nearly half of all human proteins are acetylated at their N-termini by the NatA N-terminal acetyltransferase complex. NAA10 is evolutionarily conserved as the catalytic subunit of NatA in complex with NAA15, but may also have NatA-independent functions. Several NAA10 variants are associated with genetic disorders. The phenotypic spectrum includes developmental delay, intellectual disability, and cardiac abnormalities. Here, we have identified the previously undescribed NAA10 c.303C>A and c.303C>G p.(N101K) variants in two unrelated girls. These girls have developmental delay, but they both also display hemihypertrophy a feature normally not observed or registered among these cases. Functional studies revealed that NAA10 p.(N101K) is completely impaired in its ability to bind NAA15 and to form an enzymatically active NatA complex. In contrast, the integrity of NAA10 p.(N101K) as a monomeric acetyltransferase is intact. Thus, this NAA10 variant may represent the best example of the impact of NatA mediated N-terminal acetylation, isolated from other potential NAA10-mediated cellular functions and may provide important insights into the phenotypes observed in individuals expressing pathogenic NAA10 variants.
Identifiants
pubmed: 32973342
doi: 10.1038/s41431-020-00728-2
pii: 10.1038/s41431-020-00728-2
pmc: PMC7868364
doi:
Substances chimiques
N-Terminal Acetyltransferase A
EC 2.3.1.254
NAA10 protein, human
EC 2.3.1.255
N-Terminal Acetyltransferase E
EC 2.3.1.258
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
280-288Références
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