Genotype-Renal Function Correlation in Type 2 Autosomal Dominant Polycystic Kidney Disease

Abstract

Abstract. Autosomal dominant polycystic kidney disease (ADPKD) is a common Mendelian disorder that affects approximately 1 in 1000 live births. Mutations of two genes, PKD1 and PKD2, account for the disease in approximately 80 to 85% and 10 to 15% of the cases, respectively. Significant interfamilial and intrafamilial renal disease variability in ADPKD has been well documented. Locus heterogeneity is a major determinant for interfamilial disease variability (i.e., patients from PKD1-linked families have a significantly earlier onset of ESRD compared with patients from PKD2-linked families). More recently, two studies have suggested that allelic heterogeneity might influence renal disease severity. The current study examined the genotype-renal function correlation in 461 affected individuals from 71 ADPKD families with known PKD2 mutations. Fifty different mutations were identified in these families, spanning between exon 1 and 14 of PKD2. Most (94%) of these mutations were predicted to be inactivating. The renal outcomes of these patients, including the age of onset of end-stage renal disease (ESRD) and chronic renal failure (CRF; defined as creatinine clearance Յ 50 ml/min, calculated using the Cockroft and Gault formula), were analyzed. Of all the affected individuals clinically assessed, 117 (25.4%) had ESRD, 47 (10.2%) died without ESRD, 65 (14.0%) had CRF, and 232 (50.3%) had neither CRF nor ESRD at the last follow-up. Female patients, compared with male patients, had a later mean age of onset of ESRD (76.0 [95% CI, 73.8 Linear regression and renal survival analyses revealed that the location of PKD2 mutations did not influence the age of onset of ESRD. However, patients with splice site mutations appeared to have milder renal disease compared with patients with other mutation types (P Ͻ 0.04 by log rank test; adjusted for the gender effect). Considerable renal disease variability was also found among affected individuals with the same PKD2 mutations. This variability can confound the determination of allelic effects and supports the notion that additional genetic and/or environmental factors may modulate the renal disease severity in ADPKD.

Refining Genotype-Phenotype Correlation in Autosomal Dominant Polycystic Kidney Disease

“…4 Disease progression of ADPKD is highly variable, in part because of a strong gene locus effect. [5][6][7][8] Adjusted for age, patients with PKD1 have larger kidneys and earlier onset of ESRD than patients with PKD2 (mean age at ESRD, 53.4 versus 72.7 years old, respectively). 5,6,8 Additionally, significant intrafamilial renal disease variability in ADPKD suggests a modifier effect.…”

Progressive Loss of Renal Function Is an Age-Dependent Heritable Trait in Type 1 Autosomal Dominant Polycystic Kidney Disease

“…Gene locus effect is a major determinant for interfamilial disease variability: patients from PKD1-linked families have a much earlier onset of ESRD than patients from PKD2-linked families (median age, 53 [95% confidence interval (CI), 51.2 to 54.8] vs. 69 [95% CI, 66.9 to 71.3] years) (6,7). A gender effect on renal survival (i.e., absence of ESRD) favoring the female patients is also evident in type 2 but in not type 1 ADPKD (7)(8)(9). In addition, allelic heterogeneity may have a weak effect on renal disease progression in type 1 (8) but not type 2 ADPKD (9).…”

Autosomal dominant polycystic kidney disease (ADPKD, MIM 173900, PKD1 and PKD2 genes, protein products known as polycystin-1 and polycystin-2)

“…39,40 The majority of mutations are nonsense or frameshifting and predict a truncated protein product (see Table 1 for details of mutations identified). 41,42 Although large deletions of PKD1 are described the frequency of this type of mutation is not known. A contiguous gene syndrome involving deletions of PKD1 and TSC2 has also been described where patients develop severe early-onset PKD with ESRF in childhood.…”

“…45 However, the widespread variation in clinical disease severity, especially the age of onset of renal failure, both within and between families, may be due to additional, as yet unidentified, genetic and environmental modifying factors. 42,44 This clearly makes prediction of disease severity from knowledge of the mutation alone very difficult. Germline and somatic mutations in PKD1 and PKD2 (including loss of heterozygosity) have been identified in cystic epithelia.…”