Polycystic kidney disease: Clues to pathogenesis (original) (raw)
1991, Kidney International
Autosomal-dominant polycystic kidney disease (ADPKD), largely neglected for several decades, has emerged in recent years as the renal disease most likely to be understood from the gene to the patient. Major breakthroughs have occurred in the genetics of the disorder and new experimental data is providing insights in the pathobiology of cyst formation (Table I). Genetics of ADPKD Localization of ADPKD gene Prior to 1985 information on the genetics of ADPKD was restricted to the simple concept of transmission of an autosomal dominant disorder. In 1985 Reeders et al applied the techniques of reverse genetics to this disorder and linkage was detected between the ADPKD gene and the 3' hypervariable region (3' HVR) of the alpha globin locus [I]. This linkage placed the ADPKD gene (ADPKDI) on the short arm of chromosome 16. Subsequent investigation has resulted in the development of closely-linked flanking probes which more precisely localize the gene to the tip of this chromosome [2]. This discovery which delineates the location of the ADPKD gene has enlarged the clinician's diagnostic repertoire for this disease, and provides the first step to ultimate isolation of the gene and its gene product. Prior to the availability of gene linkage analysis, the disorder and hence the gene carrier state could only be diagnosed after bilateral renal cysts were identified. This often imposed barriers to effective genetic counselling, as the cysts were frequently detected only after the childbearing years. In the last decade this barrier to early diagnosis, and hence effectively-timed genetic counselling, has been lowered substantially by the improvement of imaging techniques with more sensitive ultrasonography and the use of computed tomography and magnetic resonance imaging which permit the reliable detection of very small renal cysts [3-5]. For example, in our family studies of subjects at risk for ADPKD, 40% of children less than 20 years of age who undergo abdominal ultrasonography have detectable renal cysts, a percentage approaching the predicted frequency of 50% in an at-risk population. In other words, screening ultrasonography alone appears to detect about 80% of those who on a statistical basis are likely to have the disease. Similarly Bear et al estimate that 68% of children between ages 11 and 20 who have ADPKD have detectable cysts using ultrasonography [6]. Most recently, Parfrey et al have demonstrated that in individuals who are likely to have the ADPKD gene by linkage techniques (ADPKDI; see below) and who are
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