Germ-line mutational analysis of the TSC2 gene in 90 tuberous-sclerosis patients
- PMID: 9463313
- PMCID: PMC1376882
- DOI: 10.1086/301705
Germ-line mutational analysis of the TSC2 gene in 90 tuberous-sclerosis patients
Abstract
Ninety patients with tuberous-sclerosis complex (TSC) were tested for subtle mutations in the TSC2 gene, by means of single-strand conformational analysis (SSCA) of genomic DNA. Patients included 56 sporadic cases and 34 familial probands. For all patients, SSCA was performed for each of the 41 exons of the TSC2 gene. We identified 32 SSCA changes, 22 disease-causing mutations, and 10 polymorphic variants. Interestingly, we detected mutations at a much higher frequency in the sporadic cases (32%) than in the multiplex families (9%). Among the eight families for which linkage to the TSC2 region had been determined, only one mutation was found. Mutations were distributed equally across the gene; they included 5 deletions, 3 insertions, 10 missense mutations, 2 nonsense mutations, and 2 tandem duplications. We did not detect an increase in mutations either in the GTPase-activating protein (GAP)-related domains of TSC2 or in the activating domains that have been identified in rat tuberin. We did not detect any mutations in the exons (25 and 31) that are spliced out in the isoforms. There was no evidence for correspondence between variability of phenotype and type of mutation (missense versus early termination). Diagnostic testing will be difficult because of the genetic heterogeneity of TSC (which has at least two causative genes: TSC1 and TSC2), the large size of the TSC2 gene, and the variety of mutations. More than half of the mutations that we identified (missense, small in-frame deletion, and tandem duplication) are not amenable to the mutation-detection methods, such as protein-truncation testing, that are commonly employed for genes that encode proteins with tumor-suppressor function.
Similar articles
-
Comprehensive mutation analysis of TSC1 and TSC2-and phenotypic correlations in 150 families with tuberous sclerosis.Am J Hum Genet. 1999 May;64(5):1305-15. doi: 10.1086/302381. Am J Hum Genet. 1999. PMID: 10205261 Free PMC article. Review.
-
Analysis of both TSC1 and TSC2 for germline mutations in 126 unrelated patients with tuberous sclerosis.Hum Mutat. 1999;14(5):412-22. doi: 10.1002/(SICI)1098-1004(199911)14:5<412::AID-HUMU7>3.0.CO;2-K. Hum Mutat. 1999. PMID: 10533067
-
Molecular genetic and phenotypic analysis reveals differences between TSC1 and TSC2 associated familial and sporadic tuberous sclerosis.Hum Mol Genet. 1997 Nov;6(12):2155-61. doi: 10.1093/hmg/6.12.2155. Hum Mol Genet. 1997. PMID: 9328481
-
Germ-line mosaicism in tuberous sclerosis: how common?Am J Hum Genet. 1999 Apr;64(4):986-92. doi: 10.1086/302322. Am J Hum Genet. 1999. PMID: 10090883 Free PMC article.
-
Pathogenesis of multifocal micronodular pneumocyte hyperplasia and lymphangioleiomyomatosis in tuberous sclerosis and association with tuberous sclerosis genes TSC1 and TSC2.Pathol Int. 2001 Aug;51(8):585-94. doi: 10.1046/j.1440-1827.2001.01242.x. Pathol Int. 2001. PMID: 11564212 Review.
Cited by
-
Detection of TSC1/TSC2 mosaic variants in patients with cardiac rhabdomyoma and tuberous sclerosis complex by hybrid-capture next-generation sequencing.Mol Genet Genomic Med. 2021 Oct;9(10):e1802. doi: 10.1002/mgg3.1802. Epub 2021 Sep 4. Mol Genet Genomic Med. 2021. PMID: 34480426 Free PMC article.
-
Mutation spectrums of TSC1 and TSC2 in Chinese women with lymphangioleiomyomatosis (LAM).PLoS One. 2019 Dec 19;14(12):e0226400. doi: 10.1371/journal.pone.0226400. eCollection 2019. PLoS One. 2019. PMID: 31856217 Free PMC article.
-
Exceptional response to everolimus in a novel tuberous sclerosis complex-2 mutation-associated metastatic renal-cell carcinoma.Cold Spring Harb Mol Case Stud. 2018 Apr 2;4(2):a002220. doi: 10.1101/mcs.a002220. Print 2018 Apr. Cold Spring Harb Mol Case Stud. 2018. PMID: 29610387 Free PMC article.
-
New developments in the genetics and pathogenesis of tumours in tuberous sclerosis complex.J Pathol. 2017 Jan;241(2):219-225. doi: 10.1002/path.4827. Epub 2016 Nov 29. J Pathol. 2017. PMID: 27753446 Free PMC article. Review.
-
Mosaic and Intronic Mutations in TSC1/TSC2 Explain the Majority of TSC Patients with No Mutation Identified by Conventional Testing.PLoS Genet. 2015 Nov 5;11(11):e1005637. doi: 10.1371/journal.pgen.1005637. eCollection 2015 Nov. PLoS Genet. 2015. PMID: 26540169 Free PMC article.
References
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Molecular Biology Databases
Miscellaneous