TSC2 GAP Domain V1646Cfs*7 Variant Alters Protein Stability and Interaction Networks in Tuberous Sclerosis Complex

Area of Science:

• Neurogenetics
• Molecular Biology
• Proteostasis

Background:

• Tuberous Sclerosis Complex (TSC) is an autosomal dominant disorder.
• Caused by pathogenic variants in TSC1 or TSC2 genes.
• Characterized by neurological and developmental issues.

Purpose of the Study:

• Investigate the functional consequences of a de novo TSC2 variant (p.V1646Cfs*7).
• Elucidate the variant's impact on proteostasis.
• Provide a framework for therapeutic strategies in TSC.

Main Methods:

• Genetic testing and bioinformatics prediction.
• Protein stability assays and mass spectrometry.
• Pathway analysis and database cross-referencing.

Main Results:

• The TSC2 p.V1646Cfs*7 variant yields a truncated, initially stable protein.
• Accelerated protein degradation observed, despite retained mTOR interactions.
• Proteomics revealed enrichment in RNA metabolism and mitophagy pathways.

Conclusions:

• Altered protein stability and interaction networks contribute to TSC pathology.
• Disruptions in RNA processing and mitochondrial homeostasis are key to the TSC2 phenotype.
• Findings support precision medicine for TSC and modeling of other syndromic disorders.