Novel TSC2 mutations and decreased expression of tuberin in cultured tumor cells with an insertion mutation.

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by hamartomas in many organs. Two genes responsible for TSC, TSC1 and TSC2, were recently identified. TSC1 and TSC2 encode the proteins hamartin and tuberin, respectively, and 337 different mutations have been reported in these genes thus far. Here, we report six novel TSC2 mutations including one missense mutation, two nonsense point mutations, two frameshifts, and an insertion mutation. The insertion mutation is unique because of its location at an exon/intron boundary that results in triplication of a 34-bp sequence. Cultured tumor cells from the patient with this insertion mutation exhibited a decreased level of tuberin as revealed by Western blotting, suggesting that the mRNA of TSC2 is not translated as efficiently or the translated protein exhibits reduced stability. Five novel polymorphisms of TSC2 were also identified. As previously reported, the missense mutations were located in the GTPase activating protein-related domain of TSC2 encoded in exons 34-38. No TSC1 mutations were identified in the present subjects.