Germ-Line Mutational Analysis of the TSC2 Gene in 90 Tuberous-Sclerosis Patients

• Published in: American journal of human genetics Vol. 62; no. 2; pp. 286 - 294
• Main Authors: Au, Kit-Sing, Rodriguez, Joseph A., Finch, Jennifer L., Volcik, Kelly A., Roach, E. Steve, Delgado, Mauricio R., Rodriguez, Estanislado, Northrup, Hope
• Format: Journal Article
• Language: English
• Published: Chicago, IL Elsevier Inc 01-02-1998; University of Chicago Press
• Subjects: Adolescent; Adult; Animals; Base Sequence; Biological and medical sciences; Brain - pathology; Child; Child, Preschool; Codon - genetics; DNA Transposable Elements; Exons; Family; Frameshift Mutation; Genes, Tumor Suppressor; Genetic Linkage; Genotype-phenotype correlation; GTPase-Activating Proteins; Humans; Infant; Intellectual Disability - genetics; Kidney - pathology; Medical sciences; Mental Disorders - genetics; Middle Aged; Multigene Family; Mutation; Mutations; Neurology; Point Mutation; Polymorphism, Genetic; Polymorphism, Single-Stranded Conformational; Proteins - chemistry; Proteins - genetics; Rats; Repressor Proteins - chemistry; Repressor Proteins - genetics; Sequence Deletion; Single-strand conformational analysis (SSCA); Skin - pathology; TSC2 gene; Tuberous Sclerosis - genetics; Tuberous Sclerosis - pathology; Tuberous-sclerosis complex (TSC); Tumor Suppressor Proteins; Tumors of the nervous system. Phacomatoses; Tuberous-sclerosis complex (TSC); Mutations; TSC2 gene; Genotype-phenotype correlation; Single-strand conformational analysis (SSCA); Pseudotumor; Nervous system diseases; Sporadic; Family study; Genotype; Genetic determinism; Genetic disease; Hamartoma; Heterogeneity; Concomitant disease; Phenotype; Gene; Tumor; Benign neoplasm; Mutation; Bourneville syndrome; Locus; Comparative study; Polymorphism
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1086/301705

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.