A large TSC2 and PKD1 gene deletion is associated with renal and extrarenal signs of autosomal dominant polycystic kidney disease.

prior to the fourth or fifth decade of life. Finally, the occurrence of typical renal and extrarenal signs of Background. The renal lesions in tuberous sclerosis complex ( TSC ) consist in multiple angiomyolipomas, ADPKD in a PKD1 hemizygote individual seems to support concept that a somatic inactivation of the often associated with cysts of variable size. Recently a few TSC patients with early-onset renal cysts resem- residual PKD1 gene is required for the development of the cysts. bling the autosomal dominant polycystic kidney disease ( ADPKD) have been described. Virtually all of them Key words: autosomal dominant polycystic kidney disshowed deletions of both TSC2 and PKD1 genes. ease; contiguous TSC2 and PKD1 gene syndrome; loss Methods. Two unrelated families in which TSC and of heterozygosity analysis; tuberous sclerosis complex PKD co-segregate were investigated. 16p13.3-linked haplotype segregation, Southern blot, pulsed field gel electrophoresis, and loss of heterozygosity analyses were performed in both aected and unaected family Introduction members. Results. The proband from family 1 was first recognized TSC is an autosomal dominant hamartomatosis with as presenting typical neurological signs and skin lesions multisystem involvement [1‐3]. Renal lesions are mulof TSC and multiple renal cysts at 12 years of age. tiple angiomyolipomas often associated with cysts of Haemodialysis became necessary at age 28. CT and variable size [3‐6 ]. End-stage renal failure is rare in MRI scans revealed multiple cysts in the liver and an TSC patients and only occasionally occurs before the asymptomatic, 3‐4 mm aneurysm of the middle cereb- third decade of life [7‐12]. Recently a few sporadic ral artery. His mother, who died at 47 of breast cancer, TSC infants with early and multiple renal cysts, comhad ADPKD and reached the ESRD at 42. She showed monly seen in the advanced stages of ADPKD, have facial angiofibromas. Both patients carried a submicro- been described. The molecular defect in these patients scopic germline deletion spanning the entire TSC2 gene appears to be a deletion disrupting the genes causing and the large majority of PKD1 coding sequence. In TSC and ADPKD, known as TSC2 and PKD1 respectthe proband from family 2, the TSC diagnosis was ively [13,14]. These two genes are located only a few made at 4 years. Enlarged polycystic kidneys causing nucleotides apart, in a tail-to-tail orientation, on chroend-stage renal failure at 19 years were observed. This mosome 16p13.3 [15 ]. Here we report the clinical and patient carried a large germline, de novo deletion molecular investigation of three patients from two involving the entire TSC2 and PKD1 genes. In addition families in which both TSC and ADPKD appear to we could show in a renal hamartoma from this subject co-segregate. the loss of heterozygosity of markers spanning the TSC2 and PKD1 genes from the residual, normal chromosome 16 of paternal origin. Subjects and methods