• mild phenotype;
  • missense mutation;
  • TSC2;
  • TSC2;
  • tuberous sclerosis complex

Wentink M, Nellist M, Hoogeveen-Westerveld M, Zonnenberg B, van der Kolk D, van Essen T, Park S-M, Woods G, Cohn-Hokke P, Brussel W, Smeets E, Brooks A, Halley D, van den Ouweland A, Maat-Kievit A. Functional characterization of the TSC2 c.3598C>T (p.R1200W) missense mutation that co-segregates with tuberous sclerosis complex in mildly affected kindreds.

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by a combination of neurological symptoms and hamartomatous growths, and caused by mutations in the TSC1 and TSC2 genes. Overall, TSC2 mutations are associated with a more severe disease phenotype. We identified the c.3598C>T (R1200W) change in the TSC2 gene in seven different families. The clinical phenotypes in the families were mild, characterized by mild skin lesions, remitting epilepsy and a lack of severe mental retardation or major organ involvement. Functional analysis of the TSC2 R1200W variant, and four other TSC2 missense variants associated with a mild TSC phenotype, confirmed that the changes disrupted the TSC1–TSC2 function. Interestingly however, in each case, the TSC1–TSC2 interaction was not affected by the amino acid substitution.