Unraveling the Phenotypic and Genetic Complexity of Canine Cystinuria
Tufts' Canine and Feline Breeding and Genetics Conference, 2013
Paula S. Henthorn; Urs Giger
Section of Medical Genetics (PennGen), University of Pennsylvania, Philadelphia, PA, USA

Cystinuria is a disease of disrupted amino acid transport in the collecting ducts of the kidney failing to reclaim certain amino acids (cystine and the dibasic amino acids ornithine, lysine and arginine referred to as COLA). The increased urinary COLA concentrations reach saturation levels for cystine, which precipitates to form crystals and stones resulting in renal to urethral obstructions. Mutations in the SLC3A1 and SLC7A9 genes give rise to cystinuria in the vast majority of cystinuric humans, where the disease shows autosomal recessive or dominant inheritance (reviewed in Palacin et al. 2001; Chillaron et al. 2010).

Cystine calculi have been reported from at least 70 dog breeds, with increased incidence in several breeds (Ling et al. 1998; Osborne et al. 1999); in contrast, cystinuria is rarely seen in cats. We previously demonstrated autosomal recessively inherited cystinuria in Newfoundland dogs (with less frequent urolithiasis in females due to anatomical urological differences) caused by a mutation in the SLC3A1 gene that precludes the expression of a functional protein (Casal et al. 1995; Henthorn et al. 2000). In addition, we discovered a similar mutation in the SLC3A1 gene causing recessively inherited cystinuria, a dominantly inherited cystinuria due to a deletion in SLC3A1, and a missense mutation in SLC7A9 gene associated with persistent cystinuria and cystine stone formation in Labrador retriever, Australian cattle, and (European) miniature pinscher dogs, respectively (Brons et al. 2013). These mutations and their consequences appear to be consistent to those seen in human cystinuria.

However, for a number of other breeds examined for mutations in the SLC3A1 and SLC7A9 gene protein-coding regions, no obvious mutations have been identified (Henthorn et al. 2000; Harnevik et al. 2006; PH, UG unpublished data). In addition, it appears that in some breeds (Mastiff and related breeds, Irish terriers), only adult, intact male dogs show elevated urine COLA concentrations. In these breeds, the average age of stone formation is later than seen in male Newfoundland dogs (Giger et al. 2011a,b; PH, UG unpublished data). Most importantly, in these breeds, urinary aminoaciduria normalized after neutering, making neutering an effective treatment for cystinuria in some, but not all breeds. Neuter status has no effect on cystinuria in Newfoundlands, Labrador retrievers, Australian cattle dogs, and Miniature Pinschers (Brons et al. 2013).

For Mastiffs and related breeds, we have determined that a non-conserved amino acid substitution (Harnevik et al. 2006; PH unpublished data) as well as other DNA changes in the SLC3A1 gene that may affect the expression levels of that gene are associated with stone formation (PH, unpublished data). Intact male dogs that have two copies of this variant version of the SLC3A1 gene appear to form stones between 1 and 4 years of age (older than Newfoundlands, but younger than the average age of stone formation reported from the Minnesota stone laboratory; Osborne et al. 1999). However, not all stone-forming Mastiffs are homozygous (have two copies) of this variant allele. Additional genetic or environmental factors may play a role for cystinuria in Mastiffs. This variant SLC3A1 allele is not found in androgen-dependent cystinuric dogs of other breeds, several in which cystinuria has a relatively high incidence.

To simplify discussions of cystinuria, we have suggested a classification system for canine cystinuria that encompasses both discriminating aspects of the phenotype (for example, gender affected, androgen dependence, and mode of inheritance) and the gene associated with the disease (Brons et al. 2013; see table below). We designate type I cystinuria when the disease shows autosomal recessive inheritance, Type II when inheritance is autosomal dominant, and Type III for sex-limited/androgen-dependent inheritance (PH, UG, unpublished data). Additional types can be assigned if found. Specific mutations within each type should lead to phenotypes that are sufficiently similar that the same medical management and breeding advice applies to all cases within that type. Involvement of the SLC3A1 gene is indicated by adding - A, and similarly addendum of - B indicated involvement of mutations in SLC7A9.

Phenotype

Type I - A

Type II - A

Type II - B

Type III

Inheritance

Autosomal recessive

Autosomal dominant

Autosomal dominant

Sex-limited

Gene

SLC3A1

SLC3A1

SLC7A9

Unknown

Gender

Males and females

Males and females

Males and females

Intact adult males

Androgen dependent

No

No

No

Yes

*COLA

Homozygous

≥ 8,000

≥ 8,000

nd

≤ 4,000

Heterozygous

≤ 500

≥ 3,000

≥ 700

Breeds affected

Newfoundland
Landseer
Labrador

Aust. cattle dog

Min. Pinscher

Mastiff & related
Scot. Deerhound
Irish Terrier

DNA-based genetic test breeds

Newfoundland
Landseer
Labrador

Aust. cattle dog

Min. Pinscher

**Mastiff & related (risk for earlier stone formation)

* µmol/g creatinine, normal ≤ 500
** While we recommend DNA testing of Mastiffs and related breeds for cystinuria, be aware that this DNA test alone does not completely predict the cystinuria status of every dog (particularly for 1–2 dogs). Therefore, annual urinary nitroprusside testing is recommended for all adult intact male dogs.

While there is still much left to discover, these findings advance our understanding of this genetically complex disease. The characterization of the heterogeneity of cystinuria in different canine breeds and our proposed new classification system have important ramifications for the medical and genetic management of cystinuria in many dog breeds. Determining the molecular mechanism of cystinuria in Mastiffs and other breeds will provide insight into the genetically complex diseases. Most surprisingly, for cystinuria in some breeds, neutering can effectively cure the disease, but we caution clinicians to contact us for cases where no studies of cystinuria have yet been performed in the breed. And finally, these and future studies will have an impact on the genetic control of cystinuria in future generations of dogs.

Acknowledgements

Dr. Henthorn's cystinuria research is performed in collaboration with Dr. Urs Giger (University of Pennsylvania School of Veterinary Medicine) and Dr. Adrian Sewell (Department of Pediatrics, University Children's Hospital, Frankfurt am Main, Germany). Contributors at the University of Pennsylvania include Dr. Ann-Kathrin Brons, Caitlin Fitzgerald, Michael Raducha, JunLong Liu, and Karthik Raj. This work was supported by the University of Pennsylvania School of Veterinary Medicine, the Canine Health Foundation, the National Institutes of Health (OD 010939), the Mastiff and Scottish Deerhound national breed clubs, and by individual breeders. We thank many veterinarians, dog owners and breeders for their participation in this work.

References

1.  Brons A-K, Henthorn PS, Raj K, Fitzgerald CA, Liu J, Sewell AC, Giger U. SLC3A1 and SLC7A9 mutations in autosomal recessive or dominant canine cystinuria: a new classification system. J Vet Intern Med. Accepted for publication.

2.  Casal ML, Giger U, Bovee KC, Patterson DF. Inheritance of cystinuria and renal defect in Newfoundlands. J Am Vet Med Assoc. 1995;207:1585–1589.

3.  Chillaron J, Font-Llitjos M, Fort J, Zorzano A, Goldfarb DS, Nunes V, Palacín M. Pathophysiology and treatment of cystinuria. Nat Rev Nephrol. 2010;6:424–434.

4.  Giger U, Sewell AC, Lui J, Erat A, Sewell AC, Henthorn PS. Update on Fanconi syndrome and cystinuria in dogs: amino acidurias. In: ACVIM Forum. Denver, CO. 2011a.

5.  Giger U, Lee JW, Fitzgerald C, et al. Characterization of non-type I cystinuria in Irish terriers. J Vet Int Med. ACVIM Forum abstracts. 2011b;25:718.

6.  Harnevik L, Hoppe A, Soderkvist P. SLC7A9 cDNA cloning and mutational analysis of SLC3A1 and SLC7A9 in canine cystinuria. Mamm Genome. 2006;17:769–776.

7.  Henthorn PS, Liu J, Gidalevich T, Fang J, Casal ML, Patterson DF. Canine cystinuria: polymorphism in the canine SLC3A1 gene and identification of a nonsense mutation in cystinuric Newfoundland dogs. Hum Genet. 2000;107:295–303.

8.  Ling GV, Franti CE, Ruby AL, Johnson DL. Urolithiasis in dogs. II: breed prevalence, and interrelations of breed, sex, age, and mineral composition. Am J Vet Res. 1998;59:630–642.

9.  Osborne CA, Sanderson SL, Lulich JP, Bartges JW, Ulrich LK, Koehler LA, Bird KA, Swanson LL. Canine cystine urolithiasis. Cause, detection, treatment, and prevention. Vet Clin N Am Sm Anim Pract. 1999;29(1):193–211, xiii.

10. Palacin M, Goodyer P, Nunes V, et al. Cystinuria. In: Scriver CR, ed. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York: McGraw-Hill; 2001:4909–4932.

  

Speaker Information
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Paula S. Henthorn
Section of Medical Genetics (PennGen)
University of Pennsylvania
Philadelphia, PA, USA


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