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Categories: Renal / urinary system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 173900 (trait) , 601313 (gene)

Links to relevant human diseases in MONDO:

• MONDO:0008263: polycystic kidney disease 1

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal dominant

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2004

Cross-species summary: PKD

Species-specific name: also called Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Species-specific description: Cats with polycystic kidney disease (PKD) have large, irregularly shaped kidneys containing multiple, variably-sized epithelial-lined cysts in the cortex and medulla. PKD is associated with renal failure, frequently occurring by seven years of age. The prevalence of PKD is approximately 6% of cats worldwide. Some affected cats may also have hepatobiliary cysts, as well as biliary hyperplasia and fibrosis. The mode of inheritance is autosomal dominant. A test is available to detect the causative mutation. Edited by Vicki N. Meyers-Wallen, VMD, PhD, Dipl. ACT

Inheritance: No homozygous cats have been identified so far, suggesting the homozygous genotype is incompatible with life (Lyons et al., 2004).

Mapping: Although published after the report by Lyons et al. (2004) describing the molecular basis of this disorder, the linkage analysis described by Young et al. (2005) was the precursor of the 2004 paper, pinpointing the locus for this disorder to within 10 cR of the PKD1 locus on FCA E3.

Molecular basis: Armed with the mapping knowledge reported by Young et al. (2005), which showed this feline disorder to be closely linked to the feline PKD1 gene (mutations in which were known to be causative in other species), Lyons et al. (2004) cloned and sequenced the feline PKD1 gene, and identified the causative mutation as "a C>A transversion . . . at c.10063 (human ref NM_000296) in exon 29, resulting in a stop mutation at position 3284, which suggests a loss of approximately 25% of the C-terminus of the protein". Shitamori et al. (2023) tested 1281 cats of various breeds for the known PKD1 variant chrE3:g.42858112C>A and identified the variant in 23 cats from several breeds, while six cats diagnosed with cystic kidneys did not have the variant. "Targeted resequencing of all exons of the PKD1 was performed on the DNA of 23 cats with the conventional PKD1 variant, six cats diagnosed with cystic kidneys but without this variant, and 61 wild-type normal cats. ... [The authors] identified four variants unique to cats with cystic kidneys that were not found in wild-type normal cats, all of which were in exon 15. In particular, two (chrE:g.42848725delC, pGly1641fs and chrE:g.42850283C>T, pArg2162Trp) were candidate variants. ... The four new variants proposed in this study were only found once each in three out of six samples with cystic kidneys lacking the nonsense transversion on chrE3:g.42858112C>A. In future research, the collection of more ADPKD samples lacking the nonsense variant is required to study the frequency of the four variants."
Nowacka-Woszuk et al. (2024) report 14 affected Canadian Sphynx cats and the previously reported "causative dominant pathogenic variant (Felis_catus_9.0, NC_018738.3: chr E3:g.42858112C>A (c.9882C>A)) [omia.variant:314] in the PKD1 gene showed full concordance with clinical investigations."

Clinical features: Large irregular cystic kidneys may be identified by ultrasonography prior to onset of clinical signs associated with renal failure. Guerra et al. (2019) suggest the following diagnostic criteria using renal cyst resolution of 0.3cm for different age groups: up to 15 month of age: 1 renal cyst present; 16 to 32 month of age: 2 uni- or bilateral cysts, 33 to 49 month of age: at least 3 cysts in one of both kidneys; 50 to 66 month of age: 4 uni- or bilateral cysts using renal cyst resolution of 0.3cm (Guerra et al., 2019). Domanjko-Petri et al. (2008) suggest that in cats up to 3 month of age genotyping of the PKD1 variant is a more accurate diagnostic tool compared to ultrasonography. Renal failure develops after a variable amount of time, but onset is usually by seven years of age (range 3 – 10 years of age) (Biller et al., 1996, Eaton et al., 1997). Those developing renal failure often present with polyuria, polydipsia, palpable kidney abnormalities, inappetence, weight loss, dehydration, vomiting, lethargy; they become thin and azotemic, and develop hyperphosphatemia, isosthenuria, nonregenerative anemia, and metabolic acidosis. (Edited by Rachel Natsume 15/9/2021)

Pathology: Kidneys contain multiple, variably sized epithelial-lined cysts in the cortex and medulla. Lymphoplasmacytic inflammation and interstitial fibrosis may also be evident, suggesting chronic tubulointerstitial nephritis. Some affected cats may have small hepatobiliary cysts, as well as biliary hyperplasia and fibrosis (Biller et al., 1996). Immunohistochemical staining demonstrates incomplete translocation of Na/K ATPase from the basolateral membranes of the epithelial cells lining the cysts to the cytoplasm or the luminal membranes (Eaton et al., 1997). Domanjo-Petric et al. (2008): "Although the dysfunction of the kidney does not occur until mid to late in life, the cysts are present from birth, although are smaller in younger animals..." Guerra et al. (2019): "Most ADPKD-affected cats develop multiple bilateral renal cysts." (Edited by Rachel Natsume 15/9/2021)

Prevalence: The prevalence of PKD in Persians in Australia is 42-45% (Barrs et al., 2001), 49.2% in the United Kingdom (Cannon et al., 2001), and 37-38% worldwide (Lyons et al., 2004). In the cat population as a whole, the prevalence is approximately 6% (Grahn et al., 2004, Lyons et al., 2004). By genotyping 377 Japanese cats for the c.10063C>A variant, Sato et al. (2019) observed that "The breeds with the highest rate of the PKD1 mutation were Persian (46%), Scottish Fold (54%) and American Shorthair cats (47%). However, mixed breed cats also showed high rates of the PKD1 mutation. Of cats with the mutation, the incidence of high plasma creatinine (≥1.6 mg/dl) was greater in cats ≥3 years old, although a few cats ≥9 years of age had low plasma creatinine (<1.6 mg/dl). The coincidence of renal and hepatic cysts was 12.6%, with the high prevalence in Persian cats (31%)." Noori et al. (2019): "the prevalence of PKD was estimated 36.8% in Persian and Persian related cats in Tehran, Iran, which is approximately similar to prevalence in other parts of the world. Furthermore, there was a significant correlation between PKD and age, as in affected cats the detection probability of renal cysts in sonography was increased in older animals. For each year increase in age, the detection probability of PKD in sonography was increased about 2.62 times." From a study of the c.10063C>A variant in cats in Turkey, Bilgen et al. (2020) reported "Ten of the 12 cats with cystic kidneys were found heterozygous for the PKD1 mutation by PCR-RFLP, with DNA sequencing confirming a C→A transversion. . . . Interestingly, 6 of the 16 symptomatic cats (2 mixed-breed cats with bilateral kidney cysts, and 4 Siamese cats having renomegaly without cysts) were negative for C→A, and sequencing of the amplified region did not show any nucleotide base differentiation. None of the cats of the native breeds of Anatolia carried the mutation (35 Angora and 56 Van), nor did 9 Exotic Shorthair or 5 British Shorthair cats." Moazezi Ghavihelm et al. (2022) reported 47% of 47 Persian and Persian-related cats in Iran heterozygous for the PKD1 c.9882C>A variant (OMIA variant 314).

Control: Testing is recommended for relatives of affected cats. To prevent production of affected cats and reduce the frequency of this autosomal dominant mutation in the gene pool, cats that have the mutation should be removed from breeding programs.

Genetic testing: DNA tests (including real-time PCR and PCR-RFLP) are available to detect the mutation (Grahn et al., 2004; Lyons et al., 2004; Helps et al., 2007; Domanjko-Petric et al., 2008) (Edited by Rachel Natsume 15/9/2021)

Breeds: American Shorthair (Cat) (VBO_0100018), Burmilla (Cat) (VBO_0100056), Chartreux (Cat) (VBO_0100067), Exotic Shorthair (Cat) (VBO_0100096), Himalayan (Cat) (VBO_0100117), Maine Coon (Cat) (VBO_0100154), Oriental Shorthair (Cat) (VBO_0100184), Persian (Cat) (VBO_0100188), Persian X, Ragdoll (Cat) (VBO_0100196), Scottish Fold (Cat) (VBO_0100209), Scottish Straight (Cat) (VBO_0100213), Selkirk Rex (Cat) (VBO_0100215), Siamese (Cat) (VBO_0100221), Siberian (Cat) (VBO_0100223), Sphynx (Cat) (VBO_0100230).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: