In other species: domestic cat

Categories: Renal / urinary system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 220100 (trait) , 104614 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2000

Cross-species summary: The name of this entry has been changed from type A to follow the new expanded classification system for cystinuria suggested by Brons et al. (2013): "type I cystinuria when the disease shows autosomal recessive inheritance, type II when it shows autosomal dominant inheritance, and type III for sex-limited inheritance. . . . Involvement of the SLC3A1 gene is indicated by adding A, and similarly B indicates mutations in SLC7A9".

Species-specific name: Cystine urolithiasis

Species-specific description: Cystinuria, type 1 - A is an inherited defect that causes failure of reabsorption of cystine in the proximal renal tubule, leading to cystine precipitation in the urine. Formation of crystals and calculi lead to urolithiasis and urinary tract obstruction. The disorder is inherited as an autosomal recessive trait and it is caused by a mutation in SLC3A1. Edited by Dr. Paula Henthorn (modified by IT 23/5/2022 and 29/3/2023)

Inheritance: The mode of inheritance in Newfoundlands is autosomal recessive (Casal et al., 1995). The Labrador genotyping results of Brons et al. (2013) implied autosomal recessive inheritance in that breed. Genotyping results in English Bulldogs also suggest a recessive mode of inheritance (Harnevik et al. 2006; Ruggerone et al., 2016; Fitzwilliams et al., 2023).

Mapping: CFA10

Molecular basis: By cloning and sequencing a very likely comparative candidate gene (based on the homologous human disorder), Henthorn et al., 2000 reported the causative mutation in Newfoundlands is a C to T substitution in exon 2 [c.586C>T) of solute carrier family 3 member one (SLC3A1), which introduces a stop codon [p.Arg196*] and leads to translation of a truncated protein. Cystinuric dogs of other breeds do not have this mutation (Henthorn et al., 2000; Harvenik et al 2006). Harnevik et al. (2006): "Mutation analysis of the two cystinuria disease genes revealed one SLC7A9 mutation (A217T) and two SLC3A1 mutations (I192V and S698G) in French and English Bulldogs." The SLC3A1 variants have been suggested to be associated with cystinuria in English Bulldog by Ruggerone et al., (2016) and Fitzwilliams et al. (2023). Brons et al. (2013) reported a single bp deletion (c.350delG; p.Gly117Alafs*41) in the same gene as a causal mutation in Labradors.

Clinical features: Presenting signs include recurrent cystitis, hematuria, and stranguria. Calculi may become lodged in the urinary bladder, urethra, or kidney, causing partial or complete urinary blockage, which can result in renal failure (Brons et al., 2013). A relatively earlier age of onset has been identified in Newfoundlands compared to other breeds that develop cystinuria. Diagnosis is achieved by identifying characteristically hexagonal cystine crystals in urine sediment, or cystine calculi in stone analysis. Metabolic screening tests on urine (cyanide nitroprusside test, amino acid chromatography or amino acid quantification) can detect cystinuria before or after clinical onset. Since cystine easily precipitates in acidic urine to form uroliths, treatment includes alkalinization of the urine, high fluid intake, and drugs that increase cystine solubility (Harnevik et al., 2006). As summarised by Brons et al. (2013), Cystinuria type I - A is characterised by: occurs in males and females; not androgen-dependent; COLA [μmol/g creatinine (normal ≤500)] ≥8,000 in homozygotes and ≤500 in heterozygotes.

Pathology: Cystinuria is caused by a defect in amino acid transport in epithelial cells of the proximal tubule of the nephron and gastrointestinal epithelium. The relevant amino acids (cystine, ornithine, lysine, and arginine) are transported by a heteromeric amino acid transporter encoded by the genes SLC3A1 and SLC7A9. Clinical signs are caused by failure of reabsorption of these amino acids, leading to precipitation in the urine. In the case of cystine, it readily reaches saturation concentration in urine, which can be exacerbated by a low urinary pH. Formation of crystals and calculi lead to urolithiasis, recurrent cystitis and urinary tract obstruction. Although the transport defect also occurs in the intestine, there is no associated nutritional deficiency.

Prevalence: Cystinuria is most commonly identified in male dogs, and rarely seen in female dogs. In at least one breed, this is due to the differences in the anatomy of the urethra in males and females. Cystinuria has been most extensively studied in Newfoundlands (Henthorn et al., 2000), but various forms of cystinuria have been recognized in over 60 breeds (Osborne et al., 1999).

Control: Affected Newfoundlands are homozygous for the c.586C>T mutation, but homozygous females may be undetected clinically. Heterozygous Newfoundlands are unaffected carriers. All progeny of affected male and female Newfoundlands are carriers. It is recommended to avoid breeding that may result in affected dogs. Should carriers be bred to noncarriers, all offspring should be tested. Fitzwilliams et al. (2023) identified allele frequencies of 0.40 and 0.40 in English bulldogs from Denmark for the c.574A>G and c.2092A>G variants, respectively. The authors state: “Due to high allele frequencies, limited genetic diversity, continued uncertainty about the genetic background of cystinuria, and more severe health problems in the [English bulldog] breed, selection based on genetic testing for the mutations in SLC3A1 cannot be recommended in the Danish population of English bulldogs. However, results of the genetic test may be used as a guide to recommend prophylactic treatment.”

Breeds: English Bulldog (Dog) (VBO_0200485), French Bulldog (Dog) (VBO_0201455), Labrador Retriever (Dog) (VBO_0200800), Landseer (Dog) (VBO_0200809), Newfoundland (Dog) (VBO_0200938).
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: