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Published on: August 15, 2019
Functional assessment of TSC2 variants identified in individuals with tuberous sclerosis complex
Marianne Hoogeveen-Westerveld1, Rosemary Ekong, Sue Povey
1Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, The Netherlands.
Abstract:
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by mutations in the TSC1 or TSC2 genes. The TSC1 and TSC2 gene products, TSC1 and TSC2, form a complex that inhibits the mammalian target of rapamycin (mTOR) complex 1 (TORC1). Here, we investigate the effects of 78 TSC2 variants identified in individuals suspected of TSC, on the function of the TSC1-TSC2 complex. According to our functional assessment, 40 variants disrupted the TSC1-TSC2-dependent inhibition of TORC1. We classified 34 of these as pathogenic, three as probably pathogenic and three as possibly pathogenic. In one case, a likely effect on splicing as well as an effect on function was noted. In 15 cases, our functional assessment did not agree with the predictions of the SIFT amino acid substitution analysis software. Our data support the notion that different, nonterminating TSC2 mutations can have distinct effects on TSC1-TSC2 function, and therefore, on TSC pathology.
Insights
Tuberous sclerosis complex (TSC) is caused by TSC1/TSC2 gene mutations. This study functionally assessed 78 TSC2 variants, finding 40 disrupted the TSC1-TSC2 complex
Area of Science:
- Genetics and Molecular Biology
- Cellular Signaling Pathways
- Human Disease Genetics
Background:
- Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder.
- Mutations in TSC1 or TSC2 genes lead to TSC.
- The TSC1-TSC2 complex normally inhibits the mammalian target of rapamycin complex 1 (mTORC1).
Purpose of the Study:
- To functionally assess the impact of 78 identified TSC2 variants on TSC1-TSC2 complex function.
- To determine the pathogenicity of these variants.
- To compare functional assessment results with in silico predictions.
Main Methods:
- Functional assessment of 78 TSC2 variants in individuals suspected of TSC.
- Evaluation of the TSC1-TSC2 complex's inhibition of mTORC1.
- Classification of variant pathogenicity based on functional data.
- Comparison with SIFT amino acid substitution analysis predictions.
Main Results:
- Forty of the 78 assessed TSC2 variants disrupted TSC1-TSC2-dependent inhibition of mTORC1.
- Thirty-four variants were classified as pathogenic, three as probably pathogenic, and three as possibly pathogenic.
- Functional assessment results disagreed with SIFT predictions in 15 cases.
- One variant showed effects on both splicing and function.
Conclusions:
- Different non-terminating TSC2 mutations can exert distinct effects on TSC1-TSC2 complex function.
- These functional differences correlate with variations in TSC pathology.
- Functional assessment provides crucial data for variant classification, sometimes differing from computational predictions.
