Genetics of autosomal dominant polycystic kidney disease and mechanisms of cyst growth

INTRODUCTION

Autosomal dominant polycystic kidney disease (ADPKD) is a common disorder, occurring in approximately 1 in every 400 to 1000 live births [1,2]. It is estimated that less than one-half of these cases will be diagnosed during the patient's lifetime, as the disease is often clinically silent [1].

The genetics of ADPKD and the mechanisms of cyst growth will be reviewed here. Issues related to diagnosis and screening and of autosomal recessive polycystic kidney disease, which is a disease of children, are discussed separately. (See "Diagnosis of and screening for autosomal dominant polycystic kidney disease" and "Autosomal recessive polycystic kidney disease in children".)

GENETICS

A variety of genetic defects have been described, including frameshift, deletion and missense mutations in patients with ADPKD. Most families have an abnormality on chromosome 16 in the PKD1 locus that is tightly linked to the alpha-globin gene locus [3-6]. Most of the remaining patients have a defect in the PKD2 locus on chromosome 4 [7-9]. A few families have a defect unrelated to either locus [10-12].

Initial studies suggested that PKD1 was responsible for 96 percent of cases [3,4]. Subsequent data suggest that, at least in Europe, the incidence is lower at about 86 percent [7]. Macroscopic cysts occur later in PKD2 disease as does end-stage renal disease (mean age 74 versus 54 years in PKD1) [13]. As a result, false negative results are more likely when screening young subjects with this disorder (see below).

PKD gene products — The genes for both PKD1 and PKD2 have been identified [14-17]. PKD1 and PKD2 encode proteins called polycystin-1 and polycystin-2, respectively [14-18]. PKD1 is an extremely large and complex gene (46 exons) that generates a 14 kb mRNA, encoding a protein of over 4000 amino acids in length; PKD2 is smaller (15 exons) and encodes a protein a little smaller than 1000 amino acids in length [17].