OMIA 000256-9615 : Cystinuria, type I - A in Canis lupus familiaris

In other species: domestic cat

Possibly relevant human trait(s) and/or gene(s) (MIM number): 220100

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Recessive

Considered a defect: 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 description: Cystinuria 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 in Newfoundlands, where it is caused by a mutation in SLC3A1. Cystinuric dogs of other breeds do not have this mutation.

Edited by Dr. Paula Henthorn

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.

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).

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. 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 renal tubule and intestine. 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 has been recognized in over 60 breeds (Osborne et al., 1999). It is more common in the English bulldog, dachshund, mastiff, basset hound, Newfoundland, Staffordshire bull terrier, and French bulldog than in other breeds.

Control: Affected Newfoundlands are homozygous for the 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 affected and carrier dogs. Should carriers be bred to noncarriers, all offspring should be tested and carriers excluded from breeding.

Genetic testing: The mutation in the Newfoundland can be detected by various PCR-based tests that detect the specific base pair change (Henthorn et al., 2000). Cystinuria in Newfoundlands is a homolog of human Type 1 cystinuria (OMIM#220100), which is caused by SLC3A1 mutations. It is possible that cystinuria in other breeds may be caused by mutations in SLC7A9 (Harnevik et al, 2006), as in humans (OMIM#604144).

Breeds: Labrador, Landseer, Newfoundland.

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
SLC3A1 solute carrier family 3 (amino acid transporter heavy chain), member 1 Canis lupus familiaris 10 NC_006592.3 (46690555..46737417) SLC3A1 Homologene, Ensembl, NCBI gene

Variants

By default, variants are sorted chronologically by year of publication, to provide a historical perspective. Readers can re-sort on any column by clicking on the column header. Click it again to sort in a descending order. To create a multiple-field sort, hold down Shift while clicking on the second, third etc relevant column headers.

WARNING! Inclusion of a variant in this table does not automatically mean that it should be used for DNA testing. Anyone contemplating the use of any of these variants for DNA testing should examine critically the relevant evidence (especially in breeds other than the breed in which the variant was first described). If it is decided to proceed, the location and orientation of the variant sequence should be checked very carefully.

Breed(s) Variant Phenotype Gene Allele Type of Variant Reference Sequence Chr. g. or m. c. or n. p. Verbal Description EVA ID Year Published PubMed ID(s) Acknowledgements
Labrador Cystinuria, type I - A SLC3A1 deletion, small (<=20) c.350delG p.Gly117Alafs*41 2013 24001348
Newfoundland Cystinuria, type I -A SLC3A1 nonsense (stop-gain) CanFam3.1 10 g.46706001C>T c.586C>T p.R196* 2000 11129328 Genomic coordinates obtained from EBI's Variant Effect Predictor

References


Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.
2013 Brons, A.K., Henthorn, P.S., Raj, K., Fitzgerald, C.A., Liu, J., Sewell, A.C., Giger, U. :
SLC3A1 and SLC7A9 mutations in autosomal recessive or dominant canine cystinuria: a new classification system. J Vet Intern Med 27:1400-8, 2013. Pubmed reference: 24001348. DOI: 10.1111/jvim.12176.
2009 Houston, D.M., Moore, A.E. :
Canine and feline urolithiasis: Examination of over 50 000 urolith submissions to the Canadian veterinary urolith centre from 1998 to 2008. Canadian Veterinary Journal 50:1263–1268, 2009.
2006 Harnevik, L., Hoppe, A., Söderkvist, P. :
SLC7A9 cDNA cloning and mutational analysis of SLC3A1 and SLC7A9 in canine cystinuria. Mamm Genome 17:769-76, 2006. Pubmed reference: 16845473. DOI: 10.1007/s00335-005-0146-4.
Matos, A.J., Mascarenhas, C., Magalhães, P., Pinto, J.P. :
Efficient screening of the cystinuria-related C663T Slc3a1 nonsense mutation in Newfoundland dogs by denaturing high-performance liquid chromatography. J Vet Diagn Invest 18:102-5, 2006. Pubmed reference: 16566266.
2001 Hoppe, A., Denneberg, T. :
Cystinuria in the dog: Clinical studies during 14 years of medical treatment (vol 15, pg 361, 2001) Journal of Veterinary Internal Medicine 15:594, 2001.
2000 Henthorn, P.S., Liu, J.L., Gidalevich, T., Fang, J.K., Casal, M.L., Patterson, D.F., Giger, U. :
Canine cystinuria: polymorphism in the canine SLC3A1 gene and identification of a nonsense mutation in cystinuric Newfoundland dogs Human Genetics 107:295-303, 2000. Pubmed reference: 11129328.
1999 Osborne, C.A., Sanderson, S.L., Lulich, J.P., Bartges, J.W., Ulrich, L.K., Koehler, L.A., Bird, K.A., Swanson, L.L. :
Canine cystine urolithiasis. Cause, detection, treatment, and prevention. Vet Clin North Am Small Anim Pract 29:193-211, xiii, 1999. Pubmed reference: 10028158.
1995 Casal, M.L., Giger, U., Bovee, K.C., Patterson, D.F. :
Inheritance of cystinuria and renal defect in Newfoundlands. J Am Vet Med Assoc 207:1585-9, 1995. Pubmed reference: 7493896.
1993 Hoppe, A., Denneberg, T., Jeppsson, J.O., Kagedal, B. :
Canine Cystinuria - An Extended Study on the Effects of 2- Mercaptopropionylglycine on Cystine Urolithiasis and Urinary Cystine Excretion British Veterinary Journal 149:235-251, 1993. Pubmed reference: 8334506. DOI: 10.1016/S0007-1935(05)80170-8.
Hoppe, A., Denneberg, T., Jeppsson, J.O., Kagedal, B. :
Urinary Excretion of Amino Acids in Normal and Cystinuric Dogs British Veterinary Journal 149:253-268, 1993. Pubmed reference: 8334507. DOI: 10.1016/S0007-1935(05)80171-X.
Nash, A.S. :
Canine Cystinuria - Something Old, Something New British Veterinary Journal 149:205-206, 1993. Pubmed reference: 8334504. DOI: 10.1016/S0007-1935(05)80167-8.
1940 Brand, E., Cahill, G.F., Kassell, B. :
Canine cystinuria V. Family history of two cystinuria dogs and cystine determinates in dog urine Journal of Biological Chemistry 133:431-436, 1940.
1936 Brand, E., Cahill, G.F. :
Canine cystinuria. III Journal of Biological Chemistry 15:114-, 1936.
1823 Lassaigne, J. :
Observation sur l'existence de l'oxide cystique dans un calcul vesical du chien, et essai analytique sur la composition élémentaire de cette substance particulière. Ann Chim Phys 23:328–334, 1823.

Edit History


  • Created by Frank Nicholas on 12 Sep 2005
  • Changed by Martha MaloneyHuss on 02 Sep 2011
  • Changed by Frank Nicholas on 12 Dec 2011
  • Changed by Frank Nicholas on 15 Sep 2012
  • Changed by Frank Nicholas on 06 Sep 2013
  • Changed by Frank Nicholas on 07 Sep 2013