Molecular genetic investigation of the variability of the GTPase activating protein- (GAP-) related domain of the tuberous sclerosis-2 (TSC2) gene in TSC patients and healthy subjects
Tuberous sclerosis complex is an inherited disorder characterized by the development of benign tumors in various tissues. These tumors can affect the central nervous system, skin, kidney, heart and almost any organ. The frequency is currently estimated to be 1:6000 and the variation in severity of disease is great. Epilepsy, mental retardation, renal failure and reduced life expectancy are all possible, although a number of mildly affected persons lead normal lives with no reduction in reproductive fitness. Two genes and their products have been identified as causing TSC when they are defective: TSC1 on chromosome 9q34.3 codes for the protein hamartin and TSC2 on chromosome 16p13.3 codes for tuberin. Tuberin shows homology to GTPase activating proteins (GAPs) and hamartin and tuberin may interact with one another to control the cell cycle, suggesting a tumor suppressor function for these proteins. Efforts to screen patient populations for mutations in both genes in this study and others have been successful in identifying a large number of mutations. However, no clustering of mutations has been shown that might allow for concentration of efforts on a particular region of either gene. Sporadic mutations in TSC1 are less frequent than in TSC2 despite the fact that half of the TSC families show linkage to TSC1 and the other half to TSC2. It has been postulated that TSC1 patients are more mildly affected and may have a higher reproductive fitness than TSC2 patients. The wide distribution of mutations and the high variability in clinical manifestation of TSC further complicate the quest for genotype-phenotype correlation. If the structure and function of the protein products were clearly established, then the consequence of the great number of mutations found thus far would be known. In order to lend some context to the mutations in the patient population, a group of healthy probands was screened as a control group in exon 40 of TSC2. 29 sporadic mutations, 4 familial cases, 9 unclassified variations and 16 polymorphisms making a total of 58 variations from the wild-type sequence were found in the 70 patients examined for this project. 8 out of 25 healthy probands also demonstrated variations in sequence, which were classified as polymorphisms. The presence of these variations in the healthy population helps define them as non-disease causing. Future screening efforts may include methods of even higher sensitivity and the control of a healthy population until the gene products are better characterized. As screening efforts improve, diagnostic methods will evolve and greatly support genetic counseling. And as more is known about the function of tuberin and hamartin the closer we will come to the possibility of a causal therapy for TSC.
GAP-verwandte Domäne, Gen, Variabilität, tuberous sclerosis, mutation analysis, genetic variability, GAP-related domain
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