Categories: Renal / urinary system phene

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 260000 (trait) , 604296 (gene)

Links to MONDO diseases:

• MONDO:0009824: primary hyperoxaluria type 2

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2009

Species-specific symbol: PH2

Species-specific description: Acute-onset renal failure in young cats (<1 year of age) from deposition of oxalate crystals in renal tubules. Type II oxalosis is characterized by an increase in L-glyceric acid in the urine compared to type I oxalosis where glycolate and glyoxylate are increasingly excreted in the urine (McKerrell et al., 1989). Hyperoxaluria induces acute renal failure with recurrent calcium oxalate nephrolithiasis (Osborne et al., 2009). Cats have experienced a 10-fold increase in frequency of nephroliths in the past 20 years- of which calcium oxalate make up 70% of those uroliths (Osborne et al., 2009). Risk factors for calcium oxalate nephroliths include breed, neutered male status, 10 years of age, aciduria, hypercalciuria, hypercalcemia, hyperoxaluria, indoor status (reduced water intake, reduced urine output, obesity), and diets that are acidifying and restricting magnesium (Osborne et al., 2009; Lekcharoensuk et al. 2000). 56% of cats with uroliths suffer from chronic kidney disease (Osborne et al., 2009). (Compiled by Rachel Natsume 13/9/2021)

Molecular basis: By sequencing the most likely comparative candidate gene (based on clinical signs), Goldstein et al. (2009) identified a causal mutation as a "point mutation, G to A, . . . at the 3# splice acceptor site of intron 4". They speculated "that the lack of the necessary terminal AG sequence of intron 4 would result in a misplicing event. This would result in the splicing out of exon 5, resulting in a shortened and abnormal mRNA and protein."

Genetic engineering: Unknown
Have human generated variants been created, e.g. through genetic engineering and gene editing

Clinical features: Development of azotemia and neurological signs develop between 5 and 9 months of age (McKerrell et al., 1989). “The onset of signs was generally acute, with the development of anorexia, dehydration and weakness occurring over a few days … . Acutely ill cats were depressed, dehydrated and in poor bodily condition. Palpation of the abdomen revealed painful kidneys which were irregular in outline and frequently thought to be enlarged. In two cases the kidneys were shrunken. Deterioration was rapid...” (McKerrell et al., 1989). Generalized muscle atrophy occurs as a result of denervation of motor neurons and accumulation of neurofilaments in the spinal motor neurons (De Lorenzi et al., 2005). Spinal reflexes may be reduced to absent (De Lorenzi et al., 2005). Ethylene glycol toxicity (antifreeze) produces a similar clinical presentation of acute renal failure with histological evidence of renal oxalosis (McKerrell et al., 1989). Ultrasound examination of the kidneys can differentiate the cause of renal oxalosis by the echogenicity of the renal parenchyma. (Compiled by Rachel Natsume 13/9/2021)

Pathology: An excess of circulating oxalate accumulates in the renal tubules as calcium oxalate crystals. “Blood analysis and urinalysis showed several abnormalities, including intermittent hyperoxaluria. The L-glyceric acid concentration was remarkably increased. Electrodiagnostic tests of the peripheral nervous system were abnormal. At necropsy, generalized muscle atrophy was observed. Microscopically, both kidneys showed intraluminal birefringent oxalate crystals. Motor neuron degeneration and accumulation of neurofilaments were observed in the axons of the spinal motor neurons.” (De Lorenzi et al., 2005). There is a deficiency in DGDH liver enzyme analogous to the human form of primary hyperoxaluria type II (McKerrell et al., 1989). (Compiled by Rachel Natsume 13/9/2021)

Breeds: Burmese (Cat) (VBO_0100053), Himalayan (Cat) (VBO_0100117), Persian (Cat) (VBO_0100188).
Breeds in which the phene has been documented. For breeds in which a likely causal variant has been documented, see the variant table below

Associated gene: