Abstract
BackgroundTuberous sclerosis complex (TSC) is an autosomal dominant disorder characterised by the development of hamartomas in a variety of organs and tissues. The disease is caused by mutations in either the TSC1 gene on chromosome 9q34, or the TSC2 gene on chromosome 16p13.3. The TSC1 and TSC2 gene products, TSC1 and TSC2, form a protein complex that inhibits signal transduction to the downstream effectors of the mammalian target of rapamycin (mTOR). Recently it has been shown that missense mutations to the TSC1 gene can cause TSC.MethodsWe have used in vitro biochemical assays to investigate the effects on TSC1 function of TSC1 missense variants submitted to the Leiden Open Variation Database.ResultsWe identified specific substitutions between amino acids 50 and 190 in the N-terminal region of TSC1 that result in reduced steady state levels of the protein and lead to increased mTOR signalling.ConclusionOur results suggest that amino acid residues within the N-terminal region of TSC1 are important for TSC1 function and for maintaining the activity of the TSC1-TSC2 complex.
Highlights
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterised by the development of hamartomas in a variety of organs and tissues
To predict whether the amino acid substitutions were likely to be pathogenic, we determined the scores of the BLOSUM 62 [20] and Grantham [21] amino acid substitution matrices for all the missense variants in the LOVD TSC1 database (Figure 1A and 1B)
These scores give an indication of the differences between amino acid pairs based on amino acid composition, polarity and molecular volume, as well as substitution frequencies. Both matrices indicated that the amino acid substitutions listed in the LOVD TSC1 database in general become more conservative towards the C-terminal of TSC1
Summary
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterised by the development of hamartomas in a variety of organs and tissues. 75 85% of individuals with TSC have been shown to carry a germ-line TSC1 or TSC2 mutation [5,6,7,8,9] and a further 5 10% carry TSC1 or TSC2 variants where it is not absolutely clear from the genetic data whether the change is disease-causing (a pathogenic variant), or not (a neutral variant). To determine whether these unclassified variants are disease-causing, the effect of the changes on protein function can be investigated [10,11]. Recent studies of TSC1 missense variants identified in bladder cancers [17] and in patients with TSC [11] have shown that TSC1 amino acid substitutions can be pathogenic, reducing steady state levels of TSC1 and leading to increased mTOR activity
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