• tuberous sclerosis complex (TSC)
• diagnostic criteria
• missense mutations
• genotype-phenotype correlation
• tuberin function

• TSC, tuberous sclerosis complex

Tuberous sclerosis (TSC) is an autosomal dominant disorder caused by mutations in either the TSC1 or TSC2 gene. Both genes are tumour suppressor genes and encode the proteins hamartin and tuberin, respectively. Recent work has established that tuberin and hamartin interact to form a complex, and that this tuberin-hamartin complex antagonises signal transduction by preventing the activation of p70 S6 kinase, either directly or through mTOR.^1–3 The inhibition of p70 S6 kinase activity results in the dephosphorylation of ribosomal protein S6 and consequently leads to the down-regulation of cell growth.^4,5

The clinical manifestations of TSC vary considerably between and within families. The phenotypic spectrum ranges from minor, asymptomatic skin affections, such as hypomelanotic macules, to drug resistant epilepsy, mental retardation, and increased morbidity due to cardiac tumours, cerebral astrocytomas, renal insufficiency, and lung affections.⁶ Although some studies suggest that TSC1 mutations are more often associated with less severe disease, considerable overlap exists in the phenotypic spectrum associated with TSC1 and TSC2 mutations.^7–9

Mutations that lead to truncation of tuberin or hamartin are clearly inactivating. However, nucleotide changes that result in amino acid substitutions may be either pathogenic or, alternatively, polymorphisms that do not disrupt tuberin or hamartin function and do not cause TSC. Investigations into the effect of amino acid substitutions on tuberin can help identify important functional domains and residues, and indicate whether putative mutations are likely to be pathogenic, either by disrupting the tuberin-hamartin complex,^10,11 or by preventing the inhibition of S6 phosphorylation.¹²

We report on a family with mild signs of TSC, segregating a novel missense mutation in exon 36 of the TSC2 gene that affects tuberin function. Although the entire GAP related domain of tuberin seems to be a target for missense mutations,¹³ only few …