We have analyzed three families with ADPKD-like disease that are not explained by dominant inheritance of a single mutation to PKD1 or PKD2. Several pieces of data indicate a novel mechanism, including the pattern of inheritance and haplotypes, unusual distribution of cysts, sequence analysis of PKD1 and PKD2 and scoring of variants, and exclusion of other causes of disease. Consistent with the ADPKD-like phenotype, we provide strong data that atypical PKD1 alleles underlie the disease etiology in these families.
The inheritance pattern in M34 is consistent with autosomal dominance but it exhibits extreme differences in severity between generations. Although intrafamilial variability is seen in ADPKD,31
it does not usually range from ESRD in 60s to the minimal cyst development in the 40s, as seen here. The homozygosity of a highly conserved PKD1
mutation in the cases with ESRD, plus heterozygosity in those with a few cysts, suggested the involvement of an incompletely penetrant allele. In P192, the inheritance pattern is apparently dominant, but haplotype and sequence data again showed a PKD1
homozygous mutation associated with moderate to severe cystic disease. In the final family, M390, inheritance appears recessive and only the compound heterozygote with two highly conserved PKD1
variants has significant cystic disease.
is highly polymorphic with ~10 neutral variants found per patient from exonic sequencing.3
However, the majority are known variants, whereas most novel neutral changes are at poorly conserved sites or are conservative substitutions (Table S1
). The four variants highlighted in this study bear all the characteristics of pathogenic missense changes. This is reflected in both the Grantham matrix score and the more formal analysis of likely pathogenicity that rates them as ‘highly likely’ (Mutation Group B) or ‘likely’ (Mutation Group C)3
mutations. However, it is clear from the heterozygous phenotypes that none are fully penetrant mutations as at the most extreme they are only associated with a handful of renal cysts by middle age. We propose that these partially penetrant alleles, associated with a protein with some residual function (similar to some PKHD1
missense changes) are functionally analogous to described murine Pkd1
To prove the significance of these variants, a functional test for PC1 is required, but unfortunately no such assay yet exists. In parts of the protein (the REJ and GPS regions), the significance of missense changes has been assessed by their ability to prevent cleavage at the GPS site.32
However, the variants described here in the transmembrane region are unlikely to influence cleavage. Furthermore, as we propose that these are incompletely penetrant alleles, obtaining clear results from any functional assay may be difficult. Mimicking these changes in a mouse knock-in model (a time-consuming process) may be the only clear way to prove their significance.
Recently, a homozygous PKD2
variant, F482C, that alters polycystin-2 channel activity, was suggested to modulate disease due to a PKD1
Syndromic forms of PKD also exhibit genetic complexity, including oligogenic inheritance and phenotypic modulation by hypomorphic mutations.34-36
We propose here that specific PKD1 variants can be important in modulating cyst development. In the heterozygous state, they may be a significant cause of simple renal cysts, a small number of which often develop in normal individuals as they age.37
In unusual cases (sometimes associated with consanguinity), they can cause typical to severe PKD as a homozygote or a compound heterozygote. The pattern of inheritance may appear recessive or with large intergenerational differences in severity. The disease gene may be impossible to map in such cases, which could underlie some unlinked ADPKD families, akin to the described family with bilineal disease.17,38
These incompletely penetrant alleles could also act as a disease modifier that in trans
with an inactivating mutation can result in early onset disease, as a result of only a low level of available functional protein. These alleles would explain the recurrence risk within families, and the R2765C allele found in ~1% of alleles could be a major modulator of disease. This mechanism is unlikely to explain all early onset cases (including ones with more complex family relationships)7,39
and stochastic factors and genetic background also likely impact the severity of disease. Nevertheless, we propose that these incompletely penetrant alleles are important.
It is intriguing that the three homozygous/compound heterozygous cases had likely developmental defects of the collecting system, an abnormality rarely seen in ADPKD. The uniform pattern of multiple small cysts in the homozygous cases, as also often seen in childhood cases40
(including here), suggests that the mechanism of cystogenesis may be different than in typical, dominantly inherited PKD1. In that case, somatic events are thought to be important for cyst development;22
the wide variety in cyst size may reflect somatic changes occurring at different times, although differences in growth rates between cysts may also be important.41
The uniformity of cyst size seems to indicate that cyst initiation may have occurred at a similar time without a secondary genetic event, perhaps at a time during development when a critical level of functional PC1 is most important. Recently, conditional knockout models of Pkd1
have identified a critical period up to shortly after birth (P13d) when inactivation of both alleles results in severe cystic disease, whereas inactivation after P14d causes much milder disease.42,43
The unusual cases described here raise the question of how much a threshold level of PC1 during development may also be critical to cystogenesis in typical ADPKD patients.