TY - JOUR
T1 - Germ-line mutational analysis of the TSC2 gene in 90 tuberous-sclerosis patients
AU - Au, Kit Sing
AU - Rodriguez, Joseph A.
AU - Finch, Jennifer L.
AU - Volcik, Kelly A.
AU - Roach, E. Steve
AU - Delgado, Mauricio R.
AU - Rodriguez, Estanislado
AU - Northrup, Hope
N1 - Funding Information:
Our grateful appreciation is extended to all the families who participated in the research. Without their cooperation, this study would not have been possible. We extend our thanks to Drs. William B. Dobyns, Joan F. Atkin, and Ian J. Butler, for referral of patients and collection of samples. This work was supported by National Tuberous Sclerosis Association (NTSA) grant 97-4 (to H.N. and K.-S.A.) and by National Institute of Neurological Disorders and Stroke (NIH) grant NS32300-02 (to H.N.). J.A.R. was supported by the NTSA Manuel R. Gomez Fellowship.
PY - 1998/2
Y1 - 1998/2
N2 - 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.
AB - 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.
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U2 - 10.1086/301705
DO - 10.1086/301705
M3 - Article
C2 - 9463313
AN - SCOPUS:0031888424
SN - 0002-9297
VL - 62
SP - 286
EP - 294
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 2
ER -