Kidney International, Vol. 56 (1999), pp. 344–346

EDITORIAL

Phenotypic variability in PKD1: The family as a starting point

Autosomal dominant polycystic kidney disease over the past four years, a limited number of PKD1(ADPKD) is a systemic disorder characterized by the mutations has been reported and these lie primarily indevelopment of multiple renal cysts as well as variable the 39 unique portion of the gene (exons 33-46) [17].extrarenal manifestations, most notably involving the Very few of these mutations have been demonstratedliver and the cardiovascular system. It is the most com- in more than one family [18], suggesting that recurrentmon inherited nephropathy, with an estimated preva- mutations are uncommon among PKD1 families. How-lence in the Caucasian population of 1 in 1,000 [reviewed ever, since specific mutations have been identified in onlyin 1]. At least three different genes are involved in a subset of families, it has been difficult to determineADPKD. In populations of European origin, mutations whether underlying PKD1 mutations correlate with clin-in the PKD1 gene cause ADPKD in ,85% of families, ical disease expression in PKD1 families.whereas mutations in PKD2 cause a milder form of the In this issue of Kidney International, Hateboer et aldisease in ,15% of families [2]. At least one additional tested the hypothesis that clinical expression of PKD1-gene is responsible for the disease in the small subset related disease varies among ten large Welsh families(,1%) of families [3–5]. [19]. In each family, linkage to the PKD1 locus was

The renal cystic lesion, which may begin in utero, pro- confirmed and a unique disease-associated haplotypegresses to involve about 1 to 2% of the total nephron was identified. The authors compared affected and non-population by the fourth to fifth decade of life. These affected members of these families with respect to overallcysts and the associated kidney enlargement cause symp- survival, renal survival, as well as complications associ-toms in most ADPKD patients and lead to renal failure ated with the ADPKD phenotype. Significant interfamil-in up to 77% of affected individuals by 70 years of age ial differences were detected in both overall survival as[1]. Rarely, patients are unaware of their disease until well as renal survival. Among the common complicationsserendipitous detection occurs in the eighth or ninth associated with ADPKD, such as hypertension, macro-decade. Conversely, a small subset of patients may be scopic hematuria, urinary tract infection, renal stones,symptomatic as neonates [6]. cardiac valve abnormalities, abdominal wall hernias, and

Initial studies suggested that disease onset and pro- intracranial aneurysms, only interfamilial differences ingression followed a pattern within affected members of the prevalence of hypertension and hernias reached sta-the same family [7]. More recent experience indicates tistical significance. In comparison, no statistically sig-that ADPKD exhibits significant phenotypic variability nificant difference in the prevalence of hypertension orboth within and between families [8–10]. The variability hernias was detected among non-affected members ofbetween families may be explained in part by genetic different families. In light of the unique PKD1 haplotypeheterogeneity, that is, whether PKD1 or PKD2 muta- identified in each family, the authors speculate that thetions are segregating within the family, and in part, by observed clinical differences are most likely related todifferent mutant alleles of a given disease gene. Within different PKD1 mutations segregating in each family.PKD1 families, phenotypic variability may be explained In the study design, the authors took into accountpartially by gender [11] and partially by random somatic several potential confounding factors that are known toevents, for example, “second hits,” that inactivate the impact PKD1-related disease expression. The data werenormal PKD1 allele [12, 13].

corrected for age and gender. The potential influenceTo date, the complexity of the PKD1 genomic organi-

of environmental factors and other genetic factors notzation has significantly hindered mutational analysis.linked to the PKD1 locus, were evaluated by comparingOver two thirds of the gene sequence is duplicated inthe prevalence of ADPKD-related complications amonga more centromeric region of chromosome 16p. Threenon-affected individuals from these same families. Nogenes, the HG loci, are transcribed from this duplicatedsignificant interfamilial differences were detected. Theregion and these loci share .95% homology with exonsauthors thus speculated that differences in the preva-1-32 of the PKD1 gene [14–16]. Despite intensive effortslence of hypertension and hernias observed among af-fected individuals were due primarily to the underlying

Key words: ADPKD, renal cysts, heredity, inherited nephropathy. PKD1 mutation. As an alternative explanation, it is pos-sible that the interfamilial variability could be due to 1999 by the International Society of Nephrology

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specific epistatic interactions between the PKD1 mutant events that themselves cause severe disease? Do specificallele and another gene(s) not linked to PKD1. In other PKD1 mutations predispose to increased risk of connec-words, there could be specific interactions between the tive tissue complications as indicated by the clusteringPKD1 mutant allele and background or modifying genes of families at risk for intracranial aneurysms? If so, arein each family. Such an interaction would be manifest these mutations clustered in specific domains of theonly in affected individuals. However, each of the 10 PKD1 gene product, polycystin? Does the nature of thefamilies studied had at least 12 affected individuals. From inherited PKD1 mutations influence the rate of seconda statistical perspective, it seems more likely that the somatic events in the wild-type allele and thus, are somePKD1 phenotypes in this cohort of families would be PKD1 families more at risk for intrafamilial variabilityinfluenced by the underlying PKD1 mutation rather than in the disease phenotype? How do other genetic factorsby the cosegregation of the PKD1 gene with one or more interact with specific PKD1 mutations to modulate dis-non-linked modifying genes. ease expression? Given the complex pathogenesis in

However, it is possible that a gene or genes tightly PKD1-related disease, the answers to these and otherlinked to the PKD1 locus could contribute to the ob- questions may be slow in coming. However, the dataserved interfamilial phenotypic variability. Given its de- presented by Hateboer et al provide added incentive tosign, the current study is unable to distinguish between characterize the correlations between PKD1 genotypesthe influence on disease phenotype of a tightly linked and clinical phenotypes. In dissecting the complex patho-modifying gene versus heterogeneous PKD1 mutations genesis of PKD1-related disease, the family may be asegregating in these families. Indeed, the postulated in- logical place to start after all.fluence of specific PKD1 mutations can be established

Lisa M. Guay-Woodfordonly by the identification of actual mutations within theseBirmingham, Alabamafamilies. As noted, the genomic complexity of the 59

portion of the PKD1 gene makes such complete muta-ACKNOWLEDGMENTStional analyses difficult at the present time.

Despite this limitation, the current study provides an This editorial is supported in part by NIH award DK51034.

important contribution to our emerging understandingReprint requests to Lisa M. Guay-Woodford, M.D., Division of Ne-of PKD1-related disease expression. By demonstrating phrology, Departments of Medicine and Pediatrics, University of Ala-

interfamilial phenotypic variability among 10 large fami- bama at Birmingham, 616 Zeigler Research Building, 703 South 19thStreet, Birmingham, Alabama 35294, USA.lies with a mean of 17.5 affected individuals and 8.8 non-E-mail: lgw@uab.eduaffected individuals, the authors provide the first clear

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