Molecular Genetic Basis of Tuberous Sclerosis Complex: From Bench to Bedside

Abstract

Tuberous sclerosis complex is an autosomal dominant disease of benign tumors occurring in multiple organ systems of the body. Either of two genes, TSC1 or TSC2, can be mutated, resulting in the tuberous sclerosis complex phenotype. The protein products of the tuberous sclerosis complex genes, hamartin (TSC1) and tuberin (TSC2), have been discovered to play important roles in several cell-signaling pathways. Knowledge regarding the function of the tuberin-hamartin complex has led to therapeutic intervention trials. Numerous pathogenic mutations have been elucidated in individuals affected with tuberous sclerosis complex. Information on the type and distribution of nearly 1000 mutations in the two genes is discussed. Mosaicism for tuberous sclerosis complex mutations has been documented, complicating provision of genetic counseling to families. Emerging genotype-phenotype correlations should provide guidance for better medical care of individuals with tuberous sclerosis complex.

Genetics of Mental Retardation

“…Среди аутосомно-доминантных заболеваний, со-провождающихся умственной отсталостью, одной из частых причин является туберозный склероз -1:30 000-50 000 новорожденных [32], что составляет 0,5% от числа случаев тяжелой умственной отсталости. Ум-ственная отсталость при туберозном склерозе наблю-дается в 48% случаев [33] и варьирует от умеренной до глубокой степени.…”

Tuberous sclerosis complex and polycystic kidney disease together: An exception to the contiguous gene syndrome

“…Linkage studies were performed using genetic markers on 16p13.3 (D16S525, TSC2 5202TϾC, KG8-located in the 3= untranslated region of PKD1, D16S291, and SM7) and 9q34.3(GSN, ABL, ASS, and D9S65, which are GT repeat polymorphisms). 4,11 The results of those studies suggested that the TSC phenotypes in the proband and older sister segregated with the same inferred genotypes of the markers for both chromosomes 16p13.3 and 9q34.3. We were able to determine that the proband and older sister inherited the same copy of chromosome 16p13.3 from their father, whereas the younger sister received the other copy of the father's chromosome 16p13.3.…”

“…Hamartin and tuberin come together to form a complex that inhibits several cell signaling pathways, namely, the PI3K/PKB pathway (a growth and translation regulatory pathway), the glycogen synthase kinase 3/␤-catenin/focal adhesion kinase/Ras-related homolog pathway (which involves cell adhesion, migration, and protein transportation), and the mitogen-activated protein kinase pathway, which is involved in cell growth and proliferation. 4 Approximately two-thirds of TSC cases are caused by a de novo mutation, and the remaining are familial. 1,4 Among the familial cases of TSC, mutations in the TSC1 and TSC2 genes are found with approximately the same frequency, whereas in sporadic cases of TSC, mutations in TSC2 are much more common, 80% versus 20%, respectively.…”

“…4 Approximately two-thirds of TSC cases are caused by a de novo mutation, and the remaining are familial. 1,4 Among the familial cases of TSC, mutations in the TSC1 and TSC2 genes are found with approximately the same frequency, whereas in sporadic cases of TSC, mutations in TSC2 are much more common, 80% versus 20%, respectively. Most recent studies have found that individuals with TSC1 mutations typically have less severe disease than those with TSC2 mutations.…”

Estudo mutacional em pacientes com o complexo da esclerose tuberosa

“…Esse fenótipo pode incluir alteração de índices de proliferação celular, autossuficiência de crescimento com insensibilidade aos sinais de controle do crescimento celular, perda de capacidade de adesão ao substrato, com potencial para invasão tissular, angiogênese sustentada, etc. No caso de inativação bialélica dos genes TSC1 ou TSC2, alterações discretas do índice de proliferação celular, da adesão e do crescimento celular são observados (Au et al, 2004).…”