Mild Phenotype in Tuberous Sclerosis Patients with a Codon 905 Missense Mutation in the TSC2 Gene

Purpose: Tuberous sclerosis complex is an autosomal dominant disorder
characterised by hamartomatous growth in various organs, and
caused by mutations in the TSC1 (9q34) or TSC2 (16p13) genes. Overall,
TSC2 mutations have been associated with a more severe disease
phenotype than TSC1 mutations. We report the clinical and molecular
features in16 families with TSC2 mutations and mild phenotypes.
Method: We carried out a detailed study of the TSC phenotype and
genotype in a large French-Canadian kindred (Family A). In addition,
clinical and molecular data on 15 families with mutations at the same
codon were collected. Functional studies were performed on three different
missense mutations and related to the phenotypes.
Results: A 2714G > A (R905Q) missense mutation in exon 23 of
TSC2 was identified in 25 individuals in Family A. The TSC phenotype
in this family was unusually mild, characterised mainly by depigmented
skin lesions and by seizures that remitted spontaneously or that were
easily controlled with antiepileptic drugs. Diagnostic criteria were met
in only a minority of family members, delaying diagnosis. All other
families with the R905Q mutation were found to have a similar mild
phenotype. Patients with a 2713C > T (R905W) mutation or a 2713C >
G (R905G) mutation had a more severe phenotype. In 3 different assays,
the R905W and R905G substitutions had a more severe effect on tuberin
function than the R905Q substitution.
Conclusion: We identified 16 families with codon 905 missense
changes in TSC2. In the R905Q families, the TSC phenotype was unusually
mild, consistent with the functional studies. Our findings support
the observation that familial TSC is less severe than sporadic TSC, even
when it is due to a TSC2 mutation. Genotype-phenotype correlations indicate
that mild TSC phenotypes may be associated with specific TSC2
mutations.