Functional and structural characterisation of the TSC complex; improved functional assessment of TSC1 and TSC2 variants associated with tuberous sclerosis complex

Grant holder: Dr Mark Nellist 
: Erasmus Medical Center, The Netherlands

Project status: Ongoing – due to finish 30 June 2020

Mutations in the TSC1 and TSC2 genes cause TSC and identification of a TSC1 or TSC2 mutation is sufficient for diagnosis. However, it is not always clear whether nucleotide changes found in TSC1 or TSC2 are disease-causing. These changes are often referred to as variants of uncertain clinical significance (VUS).

TSC1 and TSC2 encode the principle components of the TSC protein complex. The aim of this project is to assess the effects on TSC complex function of TSC1 and TSC2 VUS identified in individuals with TSC. We will use gene editing technology to develop sensitive assays of TSC complex function and study the effects of TSC1 and TSC2 VUS on TSC complex activity. Demonstration of an effect on the activity of the TSC complex can help establish whether a VUS is disease-causing and provide useful information for the individuals in whom the change was identified.

Improved assays for TSC complex function will improve molecular diagnostics in TSC, help identify and characterise important structural features of the TSC complex and help investigate genotype-phenotype correlations in TSC.

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