Molecular and Functional Assessment of TSC1 and TSC2 in Individuals with Tuberous Sclerosis Complex
Tuberous sclerosis complex (TSC) is an autosomal dominant neurodevelopmental disorder and multisystem disease caused by pathogenic DNA alterations in the <i>TSC1</i> and <i>TSC2</i> tumor suppressor genes. A molecular genetic diagnosis of TSC confirms the clinical diagnosis, facilitating the implementation of appropriate care and surveillance. <i>TSC1</i> and <i>TSC2</i> 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 <i>TSC1</i> and <i>TSC2</i> variants on TORC1 activity can help establish variant pathogenicity. We searched for pathogenic alterations to <i>TSC1</i> and <i>TSC2</i> 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 <i>TSC1</i> and 88 (83%) in <i>TSC2</i>. Of these, 35 were novel. Disruption of TSC1/2 activity was demonstrated for seven <i>TSC2</i> 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.
Authors
- Ana Paula Aparecida Pereira (ORCID: https://orcid.org/0000-0002-7206-9707)
- Mark Nellist (ORCID: https://orcid.org/0000-0003-0949-1566)
- Laís Faria Masulk Cardozo (ORCID: https://orcid.org/0000-0002-8674-4152)
- Maria Rita Passos‐Bueno (ORCID: https://orcid.org/0000-0002-9248-3008)
- Santoesha Nanhoe
- Juliana Paula Gomes de Almeida (ORCID: https://orcid.org/0000-0002-5692-5577)
- Mariana Richartz Schwind (ORCID: https://orcid.org/0000-0002-5892-8499)
- Sérgio Antônio Antoniuk (ORCID: https://orcid.org/0000-0002-0678-3339)
- Luiz Gustavo Dufner‐Almeida (ORCID: https://orcid.org/0000-0003-0831-0380)
- Andréa Maria Cappellano (ORCID: https://orcid.org/0000-0002-3818-8876)
- Thiago Gerônimo Pires Alegria (ORCID: https://orcid.org/0000-0002-3086-4059)
- Silvana Chiavegatto (ORCID: https://orcid.org/0000-0001-9511-653X)
- Danielly Carvalho
- Luciana Amaral Haddad (ORCID: https://orcid.org/0000-0003-1043-8981)
- Nasjla S Silva (ORCID: https://orcid.org/0000-0002-7759-9125)
- Sérgio Rosemberg (ORCID: https://orcid.org/0000-0001-8843-8557)
Institutions
- Universidade de São Paulo (BR)
- Erasmus MC (NL)
- Irmandade da Santa Casa de Misericórdia de São Paulo (BR)
- Support group for adolescents and children with cancer (BR)
- Hospital de Clínicas Universidade Federal do Paraná (BR)
- Universidade Federal do Paraná (BR)
- Universidade Federal de São Paulo (BR)
Publication Details
- Journal
- Genes
- Published
- 2024-11-03
- DOI
- https://doi.org/10.3390/genes15111432
- Citations
- 3
- Primary Topic
- Tuberous Sclerosis Complex Research
- Type
- article
- Field-Weighted Citation Impact
- 0.98
Funders
- Tuberous Sclerosis Alliance