RESUMO
Nephronophthisis, an autosomal-recessive cystic kidney disease, is the most frequent monogenic cause for renal failure in childhood. Infantile and juvenile forms of nephronophthisis are known to originate from separate gene loci. We describe here a new disease form, adolescent nephronophthisis, that is clearly distinct by clinical and genetic findings. In a large, 340-member consanguineous Venezuelan kindred, clinical symptoms and renal pathology were evaluated. Onset of terminal renal failure was compared with that in a historical sample of juvenile nephronophthisis. Onset of terminal renal failure in adolescent nephronophthisis occurred significantly later (median age 19 years, quartile borders 16.0 and 25.0 years) than in juvenile nephronophthisis (median age 13.1 years, quartile borders 11.3 and 17.3 years; Wilcoxon test P=.0069). A total-genome scan of linkage analysis was conducted and evaluated by LOD score and total-genome haplotype analyses. A gene locus for adolescent nephronophthisis was localized to a region of homozygosity by descent, on chromosome 3q22, within a critical genetic interval of 2. 4 cM between flanking markers D3S1292 and D3S1238. The maximum LOD score for D3S1273 was 5.90 (maximum recombination fraction.035). This locus is different than that identified for juvenile nephronophthisis. These findings will have implications for diagnosis and genetic counseling in hereditary chronic renal failure and provide the basis for identification of the responsible gene.
Assuntos
Cromossomos Humanos Par 3/genética , Doenças Renais Císticas/genética , Falência Renal Crônica/genética , Adolescente , Adulto , Criança , Feminino , Humanos , Rim/patologia , Doenças Renais Císticas/patologia , Falência Renal Crônica/patologia , Escore Lod , Masculino , Repetições de Microssatélites , Pessoa de Meia-Idade , Linhagem , Reação em Cadeia da Polimerase , Análise de SobrevidaRESUMO
In this study, we report a model of spontaneous cyst formation in vitro and a procedure to obtain large quantities of cysts from polycystic rat kidney cells. Furthermore, we assess the effects of epidermal growth factor, a modulator of morphogenesis, and of taxol, a stabilizer of microtubules, which has recently been proposed as a useful treatment of human polycystic kidney disease (PKD). It is anticipated that data generated from in vitro studies using cysts from PKD-affected rat kidneys may yield further insights to the pathophysiological and cellular basis of fatal renal cyst formation processes, and may lead to specific therapeutic strategies directed at controlling the growth of cysts, thereby reducing the number of animal tests.