TSC1 and TSC2 deletions differ in size, preference for recombinatorial sequences, and location within the gene

Large TSC gene rearrangements are not rare findings in tuberous sclerosis. Interestingly, all deletions, duplications and inversions so far described involve TSC2. none being associated with TSC1. In order to shed light on th e structural basis of the preferential DNA rearrangements in TSC2 over TSC1 and to assess, in an unselected patient population, the prevalence of larg e rearrangements in both TSC loci, we screened 202 tuberous sclerosis patie nts consecutively referred at our center. Southern blot analysis on EcoRI+H indIII double-digested DNA identified 19 partial or full-length gene deleti ons: three involved TSC1 and sixteen TSC2. The breakpoint sequence of seven internal deletions, three in TSC1 and four in TSC2, allowed us to speculat e on the mechanism favoring TSC2 unequal recombinations and to identify a d eletion hot spot that lies in TSC1 and that may be relevant in the routine genetic testing of tuberous sclerosis. Briefly, three major features appear to distinguish TSC1 from TSC2 deletions: (l)deletion size: all TSC1 deleti ons are within the transcriptional unit, whereas 12 of the 16 TSC2 deletion s have at least one external breakpoint; (2) location within the gene: all TSC1 deletions are confined to the 3'end of the gene tall three 5' breakpoi nts being located in intron 20) thus resulting in the same frameshift mutat ion following amino acid K875, whereas the TSC2 internal breakpoints appear to be scattered along the gene; (3) preference for recombinatorial sequenc es: six out of eight internal TSC2 breakpoints map within Alu repeats, wher eas: none of the three TSC1 deletions appear to be Alu-mediated. Indeed, in the latter gene, unique structural features (a purine-rich tract flanked b y pyrimidine-rich segments) surrounding one of the two identified breakpoin t cluster regions might play a role in promoting inappropriate recombinatio ns.