Molecular Genetic and Phenotypic Analysis Reveals Differences between TSC1 and TSC2 Associated Familial and Sporadic Tuberous Sclerosis

Abstract

Tuberous sclerosis (TSC) is an autosomal dominant disorder characterised by the development of hamartomatous growths in many organs. Sixty to seventy percent of cases are sporadic and appear to represent new mutations. TSC exhibits locus heterogeneity: the TSC2 gene is located at 16p13.3 whilst the TSC1 gene, predicted to encode a novel protein termed hamartin, has recently been cloned from 9q34. With the exception of a contiguous gene deletion syndrome involving TSC2 and PKD1 , TSC1 and TSC2 phenotypes have been considered identical. We have now comprehensively defined the TSC1 mutational spectrum in 171 sequentially ascertained, unrelated TSC patients by single strand conformation polymorphism and heteroduplex analysis of all 21 coding exons, and by assaying a restriction fragment spanning the whole locus. Mutations were identified in 9/24 familial cases, but in only 13/147 sporadic cases. In contrast, a limited screen revealed TSC2 mutations in two of the familial cases and in 45 of the sporadic cases. Thus TSC1 mutations were significantly under-represented among sporadic cases (Fisher's exact p -value = 3.12 x 10(-4)). Both large deletions and missense mutations were common at the TSC2 locus whereas most TSC1 mutations were small truncating lesions. Mental retardation was significantly less frequent among carriers of TSC1 than TSC2 mutations (odds ratio 5.54 for sporadic cases only, 6.78 +/- 1.54 when a single randomly selected patient per multigeneration family was also included). No correlation between mental retardation and the type of mutation was found. We conclude that there is a reduced risk of mental retardation in TSC1 as opposed to TSC2 disease and that consequent ascertainment bias, at least in part, explains the relative paucity of TSC1 mutations in sporadic TSC.

Mutation analysis of the TSC1 and TSC2 genes in Japanese patients with pulmonary lymphangioleiomyomatosis

“…On the other hand, germline mutation was detected in one (4.5%) of 22 patients with sporadic LAM, whereas the majority of patients with sporadic LAM had neither of TSC1 nor TSC2 germline mutations. Our detection rate of germline mutations in patients with TSC-LAM appears to be almost identical to that of several studies on mutation analysis in patients with TSC (Au et al 1998;Jones et al 1997;Kwiatkowska et al 1998;Van Bakel et al 1997;Wilson et al 1996;Yamashita et al 2000) but lower than that of other studies (Cheadle et al 2000;Dabora et al 2001;Jones et al 1999;Niida et al 1999;Strizheva et al 2001). The detection rate varies widely from 37% to 83%, depending on the screening method used.…”

Targeted Treatments for Cognitive and Neurodevelopmental Disorders in Tuberous Sclerosis Complex

“…1,2 TSC1 and TSC2 lead to essentially identical phenotypic manifestations, although there have been some suggestions that the TSC2 phenotype is typically more severe. 3,4 The diagnosis is based on a set of clinical criteria 5 that include so-called "major" and "minor" features. Virtually every organ system in the body can be affected, but major features include facial angiofibromas, cortical tubers, subependymal nodules, cardiac rhabdomyomas, renal angiomyolipomas (AML), and lymphangioleiomyomatosis (LAM) of the lung.…”

Genotype/phenotype correlation in 325 individuals referred for a diagnosis of tuberous sclerosis complex in the United States

“…Larger studies found that a more severe phenotype was associated with TSC2 mutations. Jones et al 10,11 noted an increased prevalence of mental retardation (MR) with TSC2 mutations. Likewise, Lewis et al 12 found increased MR, autistic disorder, and infantile spasms with TSC2 mutations.…”