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Published on: August 15, 2019
Functional assessment of TSC1 missense variants identified in individuals with tuberous sclerosis complex
Marianne Hoogeveen-Westerveld1, Rosemary Ekong, Sue Povey
1Department of Clinical Genetics, Erasmus Medical Centre, 3015 GE 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). Previously, we demonstrated that pathogenic amino acid substitutions in the N-terminal domain of TSC1 (amino acids 50-224) are destabilizing. Here we investigate an additional 21 unclassified TSC1 variants. Our functional assessment identified four substitutions (p.L61R, p.G132D, p.F158S, and p.R204P) between amino acids 50 and 224 that reduced TSC1 stability and prevented the TSC1-TSC2-dependent inhibition of TORC1. In four cases (20%), our functional assessment did not agree with the predictions of the SIFT amino acid substitution analysis software. Our new data confirm our previous finding that the N-terminal region of TSC1 is essential for TSC1 function.
Insights
Pathogenic variants in the TSC1 gene can disrupt tuberous sclerosis complex (TSC) by reducing TSC1 protein stability. This study identifies four new TSC1 variants that impair TSC1-TSC2 complex function, impacting mTORC1 inhibition.
Area of Science:
- Genetics
- Molecular Biology
- Biochemistry
Background:
- Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder.
- Mutations in TSC1 or TSC2 genes cause TSC by affecting the TSC1-TSC2 complex, which regulates mTORC1 signaling.
- Previous research indicated that N-terminal TSC1 mutations (amino acids 50-224) can destabilize the protein.
Purpose of the Study:
- To functionally assess 21 unclassified TSC1 variants.
- To determine if these variants affect TSC1 stability and its interaction with TSC2.
- To investigate the impact of identified variants on mTORC1 inhibition.
Main Methods:
- Functional assessment of 21 unclassified TSC1 variants.
- Analysis of protein stability and TSC1-TSC2 complex formation.
- Evaluation of mTORC1 inhibition in the presence of variant TSC1 proteins.
- Comparison of functional assessment results with SIFT software predictions.
Main Results:
- Four novel TSC1 substitutions (p.L61R, p.G132D, p.F158S, p.R204P) within the N-terminal domain (amino acids 50-224) were identified.
- These variants reduced TSC1 protein stability.
- The identified variants impaired the TSC1-TSC2-dependent inhibition of mTORC1.
- Functional assessment results contradicted SIFT predictions in 20% of cases.
Conclusions:
- The N-terminal region of TSC1 is critical for its function.
- Pathogenic variants in this region can lead to TSC by destabilizing TSC1 and disrupting mTORC1 regulation.
- Functional assessment is crucial for classifying variants, as computational predictions may not always be accurate.
