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Molecular and Functional Assessment of TSC1 and TSC2 in Individuals with Tuberous Sclerosis Complex

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Dufner-Almeida, Luiz Gustavo ; Cardozo, Lais F. M. ; Schwind, Mariana R. ; Carvalho, Danielly ; Almeida, Juliana Paula G. ; Cappellano, Andrea Maria ; Alegria, Thiago G. P. ; Nanhoe, Santoesha ; Nellist, Mark ; Passos-Bueno, Maria Rita ; Chiavegatto, Silvana ; Silva, Nasjla S. ; Rosemberg, Sergio ; Pereira, Ana Paula A. ; Antoniuk, Sergio Antonio ; Haddad, Luciana A.
Número total de Autores: 16
Tipo de documento: Artigo Científico
Fonte: GENES; v. 15, n. 11, p. 23-pg., 2024-11-01.
Resumo

Tuberous sclerosis complex (TSC) is an autosomal dominant neurodevelopmental disorder and multisystem disease caused by pathogenic DNA alterations in the TSC1 and TSC2 tumor suppressor genes. A molecular genetic diagnosis of TSC confirms the clinical diagnosis, facilitating the implementation of appropriate care and surveillance. TSC1 and TSC2 encode the core components of the TSC1/2 complex (TSC1/2), a negative regulator of the mechanistic target of rapamycin (MTOR) complex 1 (TORC1). Functional analysis of the effects of TSC1 and TSC2 variants on TORC1 activity can help establish variant pathogenicity. We searched for pathogenic alterations to TSC1 and TSC2 in DNA isolated from 116 individuals with a definite clinical diagnosis of TSC. Missense variants and in-frame deletions were functionally assessed. Pathogenic DNA alterations were identified in 106 cases (91%); 18 (17%) in TSC1 and 88 (83%) in TSC2. Of these, 35 were novel. Disruption of TSC1/2 activity was demonstrated for seven TSC2 variants. Molecular diagnostics confirms the clinical diagnosis of TSC in a large proportion of cases. Functional assessment can help establish variant pathogenicity and is a useful adjunct to DNA analysis. (AU)

Processo FAPESP: 17/06100-8 - Suscetibilidade e resiliência aos efeitos do estresse psicossocial crônico na adolescência: estudo da participação da enzima neuronal de síntese do óxido nítrico (nNOS)
Beneficiário:Silvana Chiavegatto
Modalidade de apoio: Auxílio à Pesquisa - Regular
Processo FAPESP: 13/08028-1 - CEGH-CEL - Centro de Estudos do Genoma Humano e de Células-Tronco
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Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
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Beneficiário:Luciana Amaral Haddad
Modalidade de apoio: Auxílio à Pesquisa - Regular
Processo FAPESP: 19/10868-4 - Análise da expressão de produtos do splicing do FMR1
Beneficiário:Luciana Amaral Haddad
Modalidade de apoio: Auxílio à Pesquisa - Regular