Comprehensive mutational analysis of the TSC1 gene: observations on frequency of mutation, associated features, and nonpenetrance

Abstract

We performed a comprehensive analysis for mutations in the TSC1 gene using Southern blot analysis, and SSCP and heteroduplex analysis of amplified exons in 13 families with genetic linkage to the TSC1 region, 22 small families without linkage information, and 126 sporadic patients. 17 unique mutations were identified in 21 patients. Mutations were found in 7\13 (54 %) TSC1-linked families, 1\22 (5 %) small families without linkage, and 13 of 126 (10 %) sporadic cases. The mutations were all chain-terminating, with 14 small deletions, 1 small insertion, and 6 nonsense mutations. In families with mutations, all individuals carrying a mutation met formal diagnostic criteria for TSC, apart from a 3-year-old girl who had inherited a deletion mutation, and who had no seizures, normal intelligence, normal abdominal ultrasound, and hypomelanotic macules only on physical exam. We assessed the incidence and severity of mental retardation in the 13 sporadic patients with TSC1 mutations versus the entire sporadic cohort, and found no significant difference. The observations indicate that TSC1 mutations are all inactivating, suggest that TSC1 disease occurs in only 15-20 % of the sporadic TSC population, and demonstrate that presymptomatic TSC does occur. Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by the development of unusual tumour-like growths (hamartomas) in a variety of organ systems

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.…”

Tuberous sclerosis complex: linking growth and energy signaling pathways with human disease

“…Of the TSC2 mutations, 20% are missense or nonsense. In contrast, nearly all the reported TSC1 mutations are either nonsense or frameshift, causing premature protein truncation (Kwiatkowska et al, 1998;Jones et al, 1999;van Slegtenhorst et al, 1999;Sancak et al, 2005). Although no significant genotype-phenotype correlations have been established, patients with TSC1 mutations are less severely affected than those with TSC2 mutations (Jones et al, 1999;Dabora et al, 2001).…”

Tsc2+/– mice develop tumors in multiple sites that express gelsolin and are influenced by genetic background

“…The great majority are inactivating, causing premature truncation of the protein, and include large genomic deletions of most or all of TSC2. Mutations in TSC1 and TSC2 cause clinical features that are nearly identical; therefore, one cannot distinguish on clinical grounds between TSC1 and TSC2 disease (15)(16)(17).…”

“…More than 400 mutations have been identified in the TSC1 and TSC2 genes (1,(15)(16)(17). The great majority are inactivating, causing premature truncation of the protein, and include large genomic deletions of most or all of TSC2.…”