In other species: kangaroo , Rhesus monkey , domestic ferret , domestic cat , horse , pig , llama , taurine cattle , goat , sheep , domestic guinea pig , long-tailed chinchilla , Red shanked douc langur , Francois's langur , Dusky leaf-monkey , Siberian chipmunk , maned wolf , Silvery lutung , Javan langur , American mink

Categories: Renal / urinary system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 220150 (trait) , 606142 (gene) , 612076 (trait)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2008

Cross-species summary: Formation of calculi ('stones') in the urinary tract, or the condition associated with the presence of such calculi.

Species-specific name: Hyperuricosuria and hyperuricemia

Species-specific symbol: huu

Species-specific description: This entry focuses on hyperuricosuria and hyperuricemia and resulting urate urolithiasis. Not all dogs with hyperuricosuria and hyperuricemia will develop urolithiasis. For cystine urolithiasis see various entries for cystinuria. The reference list below includes some papers relating to other forms of urolithiasis (e.g. calcium oxalate or struvites) and it is noted that some forms of urolithiasis do not have a genetic aetiology. For example, any cause of severe hepatic dysfunction may predispose dogs to urate lithogenesis (Bartges et al., 1999).

History: All Dalmations are homozygous for a SLC2A9 mutation that causes hyperuricosuria and hyperuricemia and this mutation occurs at lower allele frequency in many other breeds.

Mapping: Linkage mapping followed by positional cloning by Bannasch et al. (2008) localised this disorder to a 2.5Mb region on chromosome CFA3. Homozygosity mapping reduced the region to 333kb, containg just four genes. By conducting a proof-of-principle across-breed GWAS on "10 total affected dogs from three breeds and 59 controls from 25 breeds", each genotyped with the Affymetrix Version 2 Custom Canine SNP (comprising 49,663 SNPs), Bannasch et al. (2010) confirmed the location of the causal gene on chromosome CFA3 first reported by Bannasch et al. (2008).

Molecular basis: Sequencing and expression analysis of one of the four positional candidate genes (see Mapping section) by Bannasch et al. (2008) identified the causal mutation as "a missense mutation (G616T;C188F)" in the SLC2A9 gene. All Dalmations are homozygous for this mutation. Karmi et al. (2010) conducted two studies in which they genotyped dogs of several other breed for this variant and identified that the variant is present with lower allele frequencies in American Staffordshire Terrier, Australian Shepherd, German Shepherd Dog, Giant Schnauzer, Parson (Jack) Russell Terrier, Labrador Retriever, Large Munsterlander, Pomeranian, South African Boerboel, Weimaraner, Bulldogs and Black Russian Terriers breeds. Cosgrove, Hammond and Mclauchlan (2015) identified the variant in Spanish Water dogs.

Clinical features: Individuals with a mutation at the SLC2A9 gene accumulate uric acid due to inefficient transport of uric acid in both the liver and renal proximal tubules (Bannasch et al., 2008). High levels of uric acid excretion predispose the formation of ammonium urate uroliths (Bartges and Callens, 2015). Clinical signs are secondary to urate urolith formation in the ureter, bladder, and urethra. Uroliths are more commonly reported in male dogs with the first episode of calculus formation in Dalmatians in males at about 4.5 years and in females at 5.5 years of age (Case et al. 1993). Affected "dogs may have pollakiuria or hematuria, or they may be asymptomatic. Small uroliths may be voided in urine, or the urine may be turbid. If urethral obstruction is present, owners may notice the dog attempting to urinate and not voiding any urine or systemic signs of obstructive uropathy (i.e., anorexia, vomiting, muscle fasciculations, depression, collapse). Urate nephroliths may be asymptomatic or may be associated with silent gross hematuria. Nephroliths that obstruct both renal pelves or both ureters are associated with systemic signs of postrenal azotemia" (Bartges et al. 1999) Systemically, hyperkalemia, metabolic acidosis, and dehydration can be observed in some animals (Bartges and Callens, 2015). IT thanks DVM student Nancy Wang, who provided the basis of this contribution in May 2023.

Breeds: American Staffordshire Terrier (Dog) (VBO_0200055), Australian Shepherd (Dog) (VBO_0200095), Bichon Frise (Dog) (VBO_0200163), Black Russian Terrier (Dog) (VBO_0200174), Boerboel (Dog) (VBO_0200185), Dalmatian (Dog) (VBO_0200427), English Bulldog (Dog) (VBO_0200485), German Hunting Terrier (Dog) (VBO_0200568), German Shepherd Dog (Dog) (VBO_0200577), Giant Schnauzer (Dog) (VBO_0200604), Labrador Retriever (Dog) (VBO_0200800), Large Munsterlander (Dog) (VBO_0200816), Lhasa Apso (Dog) (VBO_0200824), Majorca Mastiff (Dog) (VBO_0200845), Miniature Schnauzer (Dog) (VBO_0200896), Parson Russell Terrier (Dog) (VBO_0200987), Pekingese (Dog) (VBO_0200994), Pomeranian (Dog) (VBO_0201043), Poodle, Standard (Dog) (VBO_0201056), Scottish Terrier (Dog) (VBO_0201198), Spanish Water Dog (Dog) (VBO_0201280), Weimaraner (Dog) (VBO_0201401).
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: