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.

• Document type: Journal article
• Source: GENES; v. 15, n. 11, p. 23-pg., 2024-11-01.

Abstract

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)

• FAPESP's process: 17/06100-8 - Susceptibility and resilience to the effects of chronic psychosocial stress in adolescence: participation of the neuronal nitric oxide synthase (nNOS)
• Grantee: Silvana Chiavegatto
• Support Opportunities: Regular Research Grants
• FAPESP's process: 13/08028-1 - CEGH-CEL - Human Genome and Stem Cell Research Center
• Grantee: Mayana Zatz
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 11/14329-9 - Functional analyses on FMRP isoforms displaying the long, variable loop of KH2 domain
• Grantee: Luciana Amaral Haddad
• Support Opportunities: Regular Research Grants
• FAPESP's process: 19/10868-4 - Expression analysis of FMR1 splicing products
• Grantee: Luciana Amaral Haddad
• Support Opportunities: Regular Research Grants