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.

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Clinical Genetics: an international journal of genetics and molecular medicine
Department of Clinical Genetics

Wentink, M.W.J, Nellist, M.D, Hoogeveen-Westerveld, M, Zonnenberg, B.A, van der Kolk, D, van Essen, T, … Maat-Kievit, A.A. (2012). Functional characterization of the TSC2 c.3598C>T (p.R1200W) missense mutation that co-segregates with tuberous sclerosis complex in mildly affected kindreds. Clinical Genetics: an international journal of genetics and molecular medicine, 81(5), 453–461. doi:10.1111/j.1399-0004.2011.01648.x