Polycystic kidney disease as a result of loss of the tuberous sclerosis 2 tumor suppressor gene during development.
Somatic loss of function of the tuberous sclerosis 2 (TSC2) tumor suppressor gene leads to the development of benign and malignant lesions of the kidney, brain, uterus, spleen, and liver and germline loss of function of this tumor suppressor gene is embryonic lethal. In addition, the gene product of TSC2, tuberin, is necessary for normal function of the polycystic kidney disease 1 (PKD1) gene product, polycystin-1, which is required for normal cell-cell and cell-matrix interactions. We report here the development of severe polycystic kidney disease in three cases of young Eker rats carrying a germline inactivation of one allele of the Tsc2 gene. Extrarenal tumors were also noted in the spleen and uterus of these animals, which was remarkable given their young age and in the case of the spleen, diffuse involvement of the affected organ. A cell line (EKT2) was established from an affected kidney of one of these animals and used in conjunction with tissues from affected animals to elucidate the defect responsible for the development of these lesions. Affected cells were determined to have lost the wild-type Tsc2 allele while retaining two copies of chromosome 10 containing the mutant Tsc2 allele along with two normal copies of the Pkd1 gene. The genetic data, bilateral nature of the observed kidney disease, and extent of involvement of the spleen and kidney indicate that, in affected animals, loss of the wild-type Tsc2 allele occurred during embryogenesis, probably as a result of chromosome nondisjunction, with affected animals being mosaics for loss of Tsc2 gene function.
Cai
Shengli
S
Department of Carcinogenesis, The University of Texas M. D. Anderson Cancer Center, Science Park-Research Division, Smithville, Texas 78957, USA.
Everitt
Jeffrey I
JI
Kugo
Hiroyuki
H
Cook
Jennifer
J
Kleymenova
Elena
E
Walker
Cheryl Lyn
CL
D000818:Animals; D001483:Base Sequence; D015152:Blotting, Northern; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D017931:DNA Primers; D016650:Fluorescein-5-isothiocyanate; D016147:Genes, Tumor Suppressor; D005838:Genotype; D018095:Germ-Line Mutation; D006801:Humans; D007621:Karyotyping; D007889:Leiomyoma / Q000473:pathology; D009928:Organ Specificity; D007690:Polycystic Kidney Diseases / Q000235:genetics* / Q000473:pathology*; D051381:Rats; D020318:Rats, Long-Evans; D012016:Reference Values; D012097:Repressor Proteins / Q000235:genetics*; D017384:Sequence Deletion; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins
D017931:DNA Primers; D012097:Repressor Proteins; C000624653:TSC2 protein, human; C000624655:Tsc2 protein, rat; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D016650:Fluorescein-5-isothiocyanate