Incompletely penetrant PKD1 alleles suggest a role for gene dosage in cyst initiation in polycystic kidney disease

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) caused by mutations in PKD1 is significantly more severe than PKD2. Typically, ADPKD presents in adulthood but is rarely diagnosed in utero with enlarged, echogenic kidneys. Somatic mutations are thought crucial for cyst development, but gene dosage is also important since animal models with hypomorphic alleles develop cysts, but are viable as homozygotes. We screened for mutations in PKD1 and PKD2 in two consanguineous families and found PKD1 missense variants predicted to be pathogenic. In one family, two siblings homozygous for R3277C developed end stage renal disease at ages 75 and 62 years, while six heterozygotes had few cysts. In the other family, the father and two children with moderate to severe disease were homozygous for N3188S. In both families homozygous disease was associated with small cysts of relatively uniform size while marked cyst heterogeneity is typical of ADPKD. In another family, one patient diagnosed in childhood was found to be a compound heterozygote for the PKD1 variants R3105W and R2765C. All three families had evidence of developmental defects of the collecting system. Three additional ADPKD families with in utero onset had a truncating mutation in trans with either R3277C or R2765C. These cases suggest the presence of incompletely penetrant PKD1 alleles. The alleles alone may result in mild cystic disease; two such alleles cause typical to severe disease; and, in combination with an inactivating allele, are associated with early onset disease. Our study indicates that the dosage of functional PKD1 protein may be critical for cyst initiation.

Refining Genotype-Phenotype Correlation in Autosomal Dominant Polycystic Kidney Disease

“…7 PKD1 NT mutations are increasingly recognized as a distinct prognostic group with milder renal disease compared with PKD1 PT mutations. [13][14][15][16] However, our study (B) Assuming exponential growth, the rate of htTKV expansion seems similar between patients with PKD1 PT, PKD1 IF indel, and PKD2 mutations; however, the absolute htTKV (y intercept) differed between the three mutation classes. By contrast, the rate of htTKV expansion associated with NT PKD1 mutations seemed to be significantly slower than the rates of the other three mutation classes.…”

“…Thus, the mutations in these families with mild renal disease likely function as hypomorphic alleles. [13][14][15] By contrast, five families have at least one affected member who developed ESRD before age 50 years old. The mutations in these families with severe renal disease are likely completely inactivating.…”

“…More recent studies have shown a significant allelic effect in PKD1, with truncating mutations associated with severe disease and NT mutations associated with milder disease. [13][14][15][16] Here, we report the results of the Toronto Genetic Epidemiology Study of PKD (TGESP), which examined the prevalence of different mutation classes and the correlation of genotype with renal function in a prospective cohort of 220 families ascertained through probands with near-normal kidney function.…”

Mutations in Multiple PKD Genes May Explain Early and Severe Polycystic Kidney Disease

“…In line with recent data on incomplete PKD1 penetrance and normal ultrasound data of the father in this family, heterozygous PKD1 alleles like P2293L are assumed to be not sufficient to cause ADPKD but can exert an aggravating effect in concert with other changes, a hypothesis that is further corroborated by the findings obtained in the pedigrees described below. 8,9 Family D The family's propositus already displayed increased serum creatinine values and ultrasonographic features of PKD with bilaterally enlarged hyperechogenic kidneys postnatally (Figure 4). At the age of 8 years, he proceeded to ESRD and received peritoneal dialysis for almost 3 years before he was successfully transplanted.…”

“…6,7 Homozygosity for PKD1 and the coinheritance in trans of an incompletely penetrant PKD1 allele with an inactivating PKD1 mutation may explain some of the cases of early-onset PKD; however, other mechanisms for early-onset ADPKD are still unknown. 8,9 Among those cases with early-onset PKD are fetuses with Potter sequence and significant perinatal/neonatal morbidity and mortality sometimes clinically indistinguishable from those with a typical presentation of autosomal recessive polycystic kidney disease (ARPKD) and mutations in the PKHD1 gene on chromosome 6p12. 9 Several lines of evidence corroborate these clinical observations and suggest a common pathogenesis for these diseases.…”