Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 4 de 4
Filtrar
Más filtros

Banco de datos
Tipo del documento
Intervalo de año de publicación
1.
Clin Genet ; 104(3): 371-376, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37191084

RESUMEN

NAA20 is the catalytic subunit of the NatB complex, which is responsible for N-terminal acetylation of approximately 20% of the human proteome. Recently, pathogenic biallelic variants in NAA20 were associated with a novel neurodevelopmental disorder in five individuals with limited clinical information. We report two sisters harboring compound heterozygous variant (c.100C>T (p.Gln34Ter) and c.11T>C p.(Leu4Pro)) in the NAA20 gene, identified by exome sequencing. In vitro studies showed that the missense variant p.Leu4Pro resulted in a reduction of NAA20 catalytic activity due to weak coupling with the NatB auxiliary subunit. In addition, unpublished data of the previous families were reported, outlining the core phenotype of the NAA20-related disorder mostly characterized by cognitive impairment, microcephaly, ataxia, brain malformations, dysmorphism and variable occurrence of cardiac defect and epilepsy. Remarkably, our two patients featured epilepsy onset in adolescence suggesting this may be a part of syndrome evolution. Functional studies are needed to better understand the complexity of NAA20 variants pathogenesis as well as of other genes linked to N-terminal acetylation.


Asunto(s)
Microcefalia , Malformaciones del Sistema Nervioso , Adolescente , Humanos , Dominio Catalítico , Microcefalia/genética , Síndrome , Fenotipo , Acetiltransferasa B N-Terminal/genética , Acetiltransferasa B N-Terminal/metabolismo
2.
Am J Med Genet A ; 191(9): 2402-2410, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37387332

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/metabolismo
3.
Genet Med ; 23(11): 2213-2218, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34230638

RESUMEN

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.


Asunto(s)
Discapacidad Intelectual , Microcefalia , Acetiltransferasas , Humanos , Discapacidad Intelectual/genética , Microcefalia/genética , Acetiltransferasa B N-Terminal
4.
Nat Commun ; 15(1): 2269, 2024 Mar 13.
Artículo en Inglés | MEDLINE | ID: mdl-38480682

RESUMEN

Primary familial brain calcification (PFBC) is characterized by calcium deposition in the brain, causing progressive movement disorders, psychiatric symptoms, and cognitive decline. PFBC is a heterogeneous disorder currently linked to variants in six different genes, but most patients remain genetically undiagnosed. Here, we identify biallelic NAA60 variants in ten individuals from seven families with autosomal recessive PFBC. The NAA60 variants lead to loss-of-function with lack of protein N-terminal (Nt)-acetylation activity. We show that the phosphate importer SLC20A2 is a substrate of NAA60 in vitro. In cells, loss of NAA60 caused reduced surface levels of SLC20A2 and a reduction in extracellular phosphate uptake. This study establishes NAA60 as a causal gene for PFBC, provides a possible biochemical explanation of its disease-causing mechanisms and underscores NAA60-mediated Nt-acetylation of transmembrane proteins as a fundamental process for healthy neurobiological functioning.


Asunto(s)
Encefalopatías , Humanos , Acetilación , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Encefalopatías/genética , Patrón de Herencia , Mutación , Fosfatos/metabolismo , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo III/metabolismo
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA