Nephritis, X-linked (Alport syndrome)

 

Gene: COL4A5

Transmission: X-linked, recessive

For an X-linked recessive genetic disease, a male must have one copy of the mutation in question to be at risk of developing the disease.  All affected males transmit the mutation to all the females of their offspring.  A female must have two copies of the mutation in question to be at risk of developing the disease.  Females with only one copy of the mutation are not at risk of developing the disease but are carrier animals that can pass the mutation on to future generations.

Mutations:

Samoyed mutation: Substitution (nonsense), COL4A5 gene; c.3079 G>T, p.(G1027 STOP), exon35, chromosome X.

Navasota (mixed breed) mutation: Deletion, COL4A5 gene; c.513_532 del, p.(ASP 1721 frameshift), exon9, chromosome X.

Medical system: Renal

Breeds: Samoyed, Navasota (mixed breed)

Age of onset of symptoms:  2 to 3 months for proteinuria, kidney failure by 7 to 15 months.

X-linked hereditary nephropathy (XLHN), also known as X-linked nephritis or Alport Syndrome, is a sex-linked genetic disease of the kidney caused by a mutation in the COL4A5 gene. The COL4A5 gene is found on the X-chromosome and codes for an important protein subunit of Type IV collagen which is a major structural component of basement membranes.  Mutations in the COL4A5 gene can result in developmental defects in the glomerulus, leading to cystic glomerular atrophy, progressive deterioration of renal function and eventual renal failure.  Clinically this presents as blood and elevated protein levels in the urine followed by polyuria, polydipsia, weight loss, vomiting and diarrhea. Additionally, but less frequently the ocular and auditory systems can be affected.  In the Samoyed and Navasoda breed models of the XLHN, affected animals die before reaching one and half years of age due to kidney failure.

XLHN in the dog was first described in 1977 within a Samoyed pedigree and a colony of animals was maintained for medical studies.  The disease was independently identified in 2016 in a mixed dog pedigree (Navasoto breed) in, and again a colony was maintained for medical studies.

XLHN is a sex-linked genetic disease, and as such it is relatively easy to control within a breed.  It acts as a dominant disease in affected males and as a recessive disease in their carrier mothers; affected males are identified by clinical signs while carrier females are identified by having affected male progeny. As such, this disease is of academic interest but not of general concern to breeders.

 

References:
OMIA link: [1112-9615]

Caparali EB, De Gregorio V, Barua M. (2025) Genotype-based molecular mechanisms in Alport syndrome. J Am Soc Nephrol. [pm/39899372]

Cowgill LD, Segev G, Vaden S, et al (2023) Differentiation of stable kidney function versus progressive dysfunction in dogs. J Vet Intern Med 37:2241-2250. [pm/37861343]

Benali SL, Lees GE, Nabity MB, et al. (2016) X-linked hereditary nephropathy in Navasota dogs: Clinical pathology, morphology, and gene expression during disease progression. Vet Pathol 53:803-12. [pm/36917550]

Clark SD, Nabity MB, Cianciolo RE, et al. (2016) X-Linked Alport dogs demonstrate mesangial filopodial invasion of the capillary tuft as an early event in glomerular damage. PLoS One 11:e0168343. [pubmed/27959966]

Bell RJ, Lees GE, Murphy KE. (2008) X chromosome inactivation patterns in normal and X-linked hereditary nephropathy carrier dogs. Cytogenet Genome Res 122:37-40. [pubmed/18931484]
Cox ML, Lees GE, Kashtan CE, et al. (2003) Genetic cause of X-linked Alport syndrome in a family of domestic dogs. Mamm Genome 14:396- 403. [pubmed/12879362]

Zheng K, Thorner PS, Marrano P, et al. (1994) Canine X chromosome-linked hereditary nephritis: a genetic model for human X-linked hereditary nephritis resulting from a single base mutation in the gene encoding the alpha 5 chain of collagen type IV. PNAS USA 91:3989-3993. [pubmed/8171024]

Baumal R, Thorner P, Valli VEO, et al. (1991) Renal disease in carrier female dogs with x-linked hereditary nephritis. Am J Pathol. 139(4):751-64. [pubmed/1928300]
Jansen B, Valli VE, Thorner P, et al. (1987) Samoyed glomerulopathy: serial, clinical and laboratory (urine, serum biochemistry and hematology) studies. Can J Vet Res. 51(3):387-93. [pubmed/3651895]

Bernard MA, Vallli AE. (1977) Familial renal disease in Samoyed dogs.  Can Vet J. 18(7):181-9.  [pm/884645]

 

Contributed by: Mathilde Bonnier and Charlotte Dubois, Class of 2029, Faculté de médecine vétérinaire, Université de Montréal.  (Translation DWS)