A LARGE TSC2 AND PKD1 GENE DELETION IS ASSOCIATED WITH RENAL AND EXTRARENAL SIGNS OF AUTOSOMAL-DOMINANT POLYCYSTIC KIDNEY-DISEASE

Background. The renal lesions in tuberous sclerosis complex (TSC) cons ist in multiple angiomyolipomas, often associated with cysts of variab le size. Recently a few TSC patients with early-onset renal cysts rese mbling the autosomal dominant polycystic kidney disease (ADPKD) have b een described. Virtually all of them showed deletions of both TSC2 and PKD1 genes. Methods. Two unrelated families in which TSC and PKD co-s egregate were investigated. 16p13.3-linked haplotype segregation, Sout hern blot, pulsed field gel electrophoresis, and loss of heterozygosit y analyses were performed in both affected and unaffected family membe rs. Results. The proband from family 1 was first recognized as present ing typical neurological signs and skin lesions of TSC and multiple re nal cysts at 12 years of age. Haemodialysis became necessary at age 28 . CT and MRI scans revealed multiple cysts in the liver and an asympto matic, 3-4 mm aneurysm of the middle cerebral artery. His mother, who died at 47 of breast cancer, had ADPKD and reached the ESRD at 42. She showed facial angiofibromas. Both patients carried a submicroscopic g ermline deletion spanning the entire TSC2 gene and the large majority of PKD1 coding sequence. In the proband from family 2, the TSC diagnos is was made at 4 years. Enlarged polycystic kidneys causing end-stage renal failure at 19 years were observed. This patient carried a large germline, de novo deletion involving the entire TSC2 and PKD1 genes. I n addition we could show in a renal hamartoma from this subject the lo ss of heterozygosity of markers spanning the TSC2 and PKD1 genes from the residual, normal chromosome 16 of paternal origin. Conclusions. Th e presence of a deletion involving both TSC2 and PKD1 genes should be considered in the clinical assessment of TSC children with an early-on set polycystic kidney disease, and more generally in all ADPKD patient s who develop end-stage renal failure prior to the fourth or fifth dec ade of life. Finally, the occurrence of typical renal and extrarenal s igns of ADPKD in a PKD1 hemizygote individual seems to support concept that a somatic inactivation of the residual PKD1 gene is required for the development of the cysts.