RESUMEN
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.
Asunto(s)
Trastorno del Espectro Autista , Discapacidad Intelectual , Masculino , Humanos , Preescolar , Acetiltransferasas N-Terminal/metabolismo , Secuencia de Aminoácidos , Proteómica , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , Acetiltransferasa C N-Terminal/genética , Acetiltransferasa C N-Terminal/metabolismoRESUMEN
Family physicians (FPs) will encounter genetic concerns within community practice. To determine how FPs compare to genetic counselors (GCs), a cross-sectional survey was distributed to Canadian FPs and GCs in 2019. The survey assessed risk analysis, counseling, and management of genetic information. FPs performed less well than GCs on each survey question and scenario (p < 0.05). Average overall survey scores for FPs were lower than GCs (62% vs. 93%, p < 0.001). Additional genetic training for FPs may help avoid potential harm.