Polycystic kidney disease (PKD) is a heterogeneous group of monogenic disorders characterized by the bilateral formation and progressive expansion of renal cyst that lead to end stage renal disease (ESRD) (1). Several Mendelian diseases including autosomal dominant polycystic kidney disease (ADPKD), autosomal recessive polycystic kidney disease (ARPKD), and atypical forms of PKD can be grouped under this pathological entity.

Autosomal dominant polycystic kidney disease is the most common inherited kidney disease affecting ~1/400–1/1,000 individuals (2). The hallmark characteristic of ADPKD is the progressive development and expansion of cysts in the kidney leading to ESRD. It can be associated with several extrarenal manifestations including hypertension, symptomatic extrarenal cysts, and subarachnoid hemorrhage from intracranial aneurysms (3–5). The vast majority of the patients develop the disease between the ages of 20–40 s, but there have been sporadic cases that range in onset from late to childhood (“early onset,” before 15 years old) or even in utero (“very early onset”) (6).

Autosomal dominant polycystic kidney disease is genetically heterogeneous and associated with mutations in PKD1 (responsible of ADPKD-Type I), PKD2 (-Type II), and GANAB. PKD1 is a complex gene mapping to chromosome 16 (16p13.3) (Figure 1A). Its genomic structure has a number of features that complicate its evaluation (7, 8): (a) it is highly GC-rich with a large number of CpG dinucleotides, (b) 70% of PKD1 is duplicated multiple times throughout chromosome 16 with high sequence fidelity (95% identity) (9), and (c) it contains a 2.5 kb polypyrimidine tract in intron 21 (the largest in the human genome) (10). In contrast to PKD1, the PKD2 gene is located on chromosome 4 (4q21) and has simpler features and structure (11) (Figure 1A). Approximately, 80–85% of ADPKD families were associated with PKD1 mutations, and 15–20% to PKD2 mutations in the literature (12). Recently, Porath and colleagues identified causal mutations in GANAB, a gene on chromosome 11q12.3 (Figure 1A), in ADPKD patients that are negative for PKD1 and PKD2 mutations. They report that GANAB accounts for ~0.3% of total ADPKD and it is associated with a milder manifestation of PKD and autosomal dominant polycystic liver disease (ADPLD) (5).

The diagnosis of ADPKD is dependent on the stage of the disease. When the disease is fully established, the diagnosis is clinically based on patient’s history and physical examination (13, 14). However, definitive diagnosis can be difficult due to other disorders having overlapping symptoms. Therefore, complementary approaches such as diagnostic imaging or genetic tests are necessary to confirm the diagnosis. Imaging techniques, including ultrasound, computed axial tomography, or nuclear magnetic resonance, allow for the detection of cysts in the kidney, liver, or pancreas (15). The magnetic resonance technique has proven to be more sensitive than ultrasound, allowing measurements of height-adjusted total kidney volume (htTKV) and better definition of the cysts without the use of contrast agents. However, these imaging tests are expensive (16) and are often not performed on a subset of the ADPKD population including those who are young individuals at risk or patients with atypical or de novo renal cystic disease (13) for whom complementary genetic tests is the method for definitive diagnosis. Direct DNA sequencing (DS) could offer a molecular diagnosis; however, the genetic analysis of the PKD1 (responsible for most ADPKD cases) is complicated. The 5′-region of the gene (exon 1–34) is replicated in at least six highly homologous copies on chromosome 16 (7, 9, 17). To date, direct sequencing based on a Long-Rage PCR strategy with specific primers has been the accepted strategy by the ADPKD community (18). Isolated gene by gene sequencing is laborious and expensive, and provides limited amount of information to provide a better diagnosis and prognosis for the patients. Moreover, it has been described that the main mutation responsible of the disease may interact with other PKD or ciliopathy loci modifying the phenotype and extending the genetic complexity of the disease (18–20). For this reason, ADPKD experts are highlighting the necessity to screen all cystic genes in a common strategy to allow for a more accurate diagnosis, including those genes responsible of atypical forms of PKD. Under this context, next-generation sequencing strategies followed by the validation of variants by DS have become the recommended methodology allowing for faster, more cost-effective, and more reliable genetic diagnosis of large ADPKD cohorts (21).

It has been described that patients with mutations in PKD1 gene have larger kidneys and earlier onset (mean age at ESRD, 53.4 versus 72.7 years old, respectively) with lower eGFR and higher htTKV than PKD2 patients (22, 23). In addition, GANAB mutations seem to be associated with a mild renal phenotype, closer to a PKD2 than a PKD1 phenotype, revealing the importance of molecular diagnosis (5). Moreover, a strong correlation between the type of the mutation and the severity of the disease was observed, illustrating the importance of quantifying genetic heterogeneity in ADPKD. Truncating PKD1 mutations (frameshift, splicing, and nonsense) have a more severe disease prognosis with lower eGFR; however. the type of mutation does not correlate with htTKV (23, 24). Non-truncating PKD1 mutations (missense, inframe deletion/insertion) or mutations in PKD2 are associated with a milder form of the disease. In addition, males with truncating PKD1 are associated with larger kidneys and increased risk for ESRD, while women with truncating PKD1 have a more severe liver phenotype (23, 24). In addition, disease manifestation in ADPKD patients from the same family, or patients with the same mutation, can have varying severity and differential disease progression, which may be due to the presence of variation in a modifying gene. This phenomenon is known as genetic interaction and epistasis, and usually aggravates or attenuates the phenotype cause by the primary mutation (17, 25).

Based on genetic and clinical data, Cornec-Le Gall and colleagues (26) developed a robust prognostic model, the PROPKD score (with a range from 0 to 9), to predict survival in ADPKD patients. They described critical variables associated with ESRD including age of onset (median age reported to be 70.6 years for low risk, 56.9 years for intermediate risk, and 49 years for high risk) and a scoring system to predict disease progression: sex (being male 1 point), need for antihypertensive therapy before 35 years old (2 points), occurrence of the first urologic event before 35 years old (2 points), and genetic status (having PKD2 mutations: 0 points, non-truncating PKD1 mutation: 2 points and truncating PKD1 mutations: 4 points). Three risk categories were then defined to describe the putative risk for progression to ESRD: low risk (0–3 points), intermediate risk (4–6 points), and high risk (7–9 points) (26).

PKD1 and PKD2 encode the proteins PC1/Polycystin-1 and PC2/Polycystin-2 or TRPP2, respectively. PC1 is a putative receptor for an unidentified ligand which contains a long extracellular N-terminal domain, 11 transmembrane domains and a short intracellular C-terminal domain (27). PC2/TRPP2 has similar characteristics to TRP channel, having six transmembrane segments, a pore loop domain (separating the first two transmembrane segments), and an N- and C-terminal domains (28) (Figure 1B). PC2 is a Ca²⁺-permeable non-selective ion cation channel and together with PC1 forms a receptor–channel complex implicated in the Ca²⁺ pathway called PC complex (29).

In contrast to PKD1 and PKD2, GANAB encodes the alpha subunit of glucosidase II (GIIα) which is the catalytic subunit of GII. GIIα together with the regulatory subunit of GII, GIIβ (also called hepatocystin) (5) form a functional holoenzyme in the endoplasmic reticulum (ER). This holoenzyme is implicated in the proper folding and translocation of glycoproteins into the ER, and its dysfunction has been reported to be associated with maturation and localization defects of PC1 (30).

In the last two decades, there have been significant contributions toward our understanding of the genetic, cellular, and functional role of PKD genes and proteins, as well as, the identification of a number of pathways implicated in the pathogenesis of the disease. Nevertheless, several questions remain unresolved and controversial in the PKD community. The complexity of this disease is reflected along all scientific levels, starting at the genetic level with critical refinement of the mutations, followed by the study of protein function and dosage to understand the spectrum of clinical manifestations in PKD, and finally the study of related pathways and modifier mechanisms that all should be taken into account for future clinical trials and personalized medicine.

All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.