Predicted Mutation Strength of Nontruncating PKD1 Mutations Aids Genotype-Phenotype Correlations in Autosomal Dominant Polycystic Kidney Disease

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) often results in ESRD but with a highly variable course. Mutations to PKD1 or PKD2 cause ADPKD; both loci have high levels of allelic heterogeneity. We evaluated genotype-phenotype correlations in 1119 patients (945 families) from the HALT Progression of PKD Study and the Consortium of Radiologic Imaging Study of PKD Study. The population was defined as: 77.7% PKD1, 14.7% PKD2, and 7.6% with no mutation detected (NMD). Phenotypic end points were sex, eGFR, height-adjusted total kidney volume (htTKV), and liver cyst volume. Analysis of the eGFR and htTKV measures showed that the PKD1 group had more severe disease than the PKD2 group, whereas the NMD group had a PKD2-like phenotype. In both the PKD1 and PKD2 populations, men had more severe renal disease, but women had larger liver cyst volumes. Compared with nontruncating PKD1 mutations, truncating PKD1 mutations associated with lower eGFR, but the mutation groups were not differentiated by htTKV. PKD1 nontruncating mutations were evaluated for conservation and chemical change and subdivided into strong (mutation strength group 2 [MSG2]) and weak (MSG3) mutation groups. Analysis of eGFR and htTKV measures showed that patients with MSG3 but not MSG2 mutations had significantly milder disease than patients with truncating cases (MSG1), an association especially evident in extreme decile populations. Overall, we have quantified the contribution of genic and PKD1 allelic effects and sex to the ADPKD phenotype. Intrafamilial correlation analysis showed that other factors shared by families influence htTKV, with these additional genetic/environmental factors significantly affecting the ADPKD phenotype.

Isolated polycystic liver disease genes define effectors of polycystin-1 function

“…Once PC1 activity falls below a threshold, the rate of cyst progression is directly related to the degree of impairment of PC1 activity. This continuum also applies to ADPKD (43,44), but bile ducts appear to have a lower tolerance for reduced PC1 dosage compared with kidney tubules. This can be due to either a higher threshold requirement or a lower baseline level of PC1 activity in bile duct cells, which may explain the occurrence of PCLD rather than ADPKD with genetic defects affecting PC1 biogenesis.…”

Polycystin 2-dependent cardio-protective mechanisms revealed by cardiac stress

“…PC1 and PC2 form a heteromeric molecular complex in the plasma and ciliary membranes, where it is proposed that PC1 serves as a mechanosensor and PC2 functions as a calcium permeable channel [36]. Mutations in pkd1 are found in 85% of ADPKD cases, which typically have an earlier onset and more severe phenotype than those with mutations in pkd2 , accounting for 15% of cases [13]. Regardless of the causative mutation, ADPKD is associated with a high risk of cardiovascular complications, where 90% of ADPKD patients exhibit cardiac hypertrophy at the time of death [8, 34].…”

Ciliary Mechanisms of Cyst Formation in Polycystic Kidney Disease

“…Mature forms of both proteins localize to the primary cilium, a minute membrane-encased microtubule-based structure that protrudes from the apical surface of kidney tubule epithelial cells (Pazour et al 2002;Yoder et al 2002) that is used by cells as a sensory organelle for signal integration. Mutations in PKD1 account for 78% of ADPKD cases, mutations in PKD2 account for the 15% of cases, and the remaining 7% -8% of cases have no mutation detected in either gene (Audrezet et al 2012;Heyer et al 2016). PC1 is a 4302-amino-acid protein consisting of a large 3000-amino-acid extracellular domain, 11 transmembrane domains, and an intracellular carboxyl terminus.…”

“…The most extreme level is total loss of function, which occurs when both the germline PKD gene mutation and the second hit mutation result in complete loss of functional polycystin protein. A subset of germline nonsynonymous amino-acid substitution mutations in PC1 have reduced but not absent function (i.e., hypomorphic alleles), and these result in a milder course for ADPKD (Hopp et al 2012;Cornec-Le Gall et al 2013;Heyer et al 2016). These hypomorphic alleles typically produce intact PC1 protein that may be relatively deficient in one of several putative functions.…”