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











Base de dados
Tipo de estudo
Intervalo de ano de publicação
1.
FEBS J ; 287(22): 4848-4861, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32150788

RESUMO

Germline mutation in the PTEN gene is the genetic basis of PTEN hamartoma tumor syndrome with the affected individuals harboring features of autism spectrum disorders. Characterizing a panel of 14 autism-associated PTEN missense mutations revealed reduced protein stability, catalytic activity, and subcellular distribution. Nine out of 14 (64%) PTEN missense mutants had reduced protein expression with most mutations confined to the C2 domain. Selected mutants displayed enhanced polyubiquitination and shortened protein half-life, but that did not appear to involve the polyubiquitination sites at lysine residues at codon 13 or 289. Analyzing their intrinsic lipid phosphatase activities revealed that 78% (11 out of 14) of these mutants had twofold to 10-fold reduction in catalytic activity toward phosphatidylinositol phosphate substrates. Analyzing the subcellular localization of the PTEN missense mutants showed that 64% (nine out of 14) had altered nuclear-to-cytosol ratios with four mutants (G44D, H123Q, E157G, and D326N) showing greater nuclear localization. The E157G mutant was knocked-in to an induced pluripotent stem cell line and recapitulated a similar nuclear targeting preference. Furthermore, iPSCs expressing the E157G mutant were more proliferative at the neural progenitor cell stage but exhibited more extensive dendritic outgrowth. In summary, the combination of biological changes in PTEN is expected to contribute to the behavioral and cellular features of this neurodevelopmental disorder.


Assuntos
Transtorno do Espectro Autista/genética , Núcleo Celular/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Mutação de Sentido Incorreto , Crescimento Neuronal/genética , PTEN Fosfo-Hidrolase/genética , Transtorno do Espectro Autista/metabolismo , Western Blotting , Linhagem Celular Tumoral , Células HEK293 , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Células PC-3 , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidato Fosfatase/genética , Fosfatidato Fosfatase/metabolismo , Fosforilação , Estabilidade Proteica
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA