OMIA 001112-9615 : Nephritis, X-linked in Canis lupus familiaris

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 301050 , 303630

Mendelian trait/disorder: yes

Mode of inheritance: X-linked

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 1994

Species-specific name: Alport syndrome

Species-specific symbol: HN

Species-specific description: X-linked nephritis is caused by mutations in the alpha 5 chain of collagen type IV (COL4A5), a key structural component of the glomerular basement membrane. Affected males have severely reduced COL4A5 levels and early-onset renal failure.

Mapping: CFX

Molecular basis: The causative mutation in the Samoyed is a G to T substitution in exon 35 of COL4A5, which generates a premature stop codon (Zheng et al., 1994). The causative mutation in the Navasota mixed breed model is a 10 base pair deletion in exon 9 of COL4A5, which generates a premature stop codon. In the Navasota model, the mutant genotype at this locus has no apparent effect on X inactivation in females (Bell et al., 2008).

Clinical features: Affected males exhibit proteinuria and develop rapidly progressive renal failure, which is usually fatal before 1 year of age in the Samoyed, and 18 months of age in the Navasota mixed breed model. Heterozygous female Samoyeds may present with a wide range of renal function, from normal to initially having proteinuria and occasionally microscopic hematuria, but most were healthy until 5 years of age (Baumal et al., 1991). With age, approximately 31% of carrier female Samoyeds developed mild renal disease, and 38% progressed to end-stage renal disease.

Pathology: Collagen type IV is an important contributor to basement membrane structural integrity. Affected males have approximately 10% of normal levels of the alpha 5 chain of collagen type IV, as well as decreased levels of the alpha 3 and alpha 4 chains (Thorner et al., 1996). Multilaminar splitting of glomerular basement membranes is found by electron microscopy. Areas of focal segmental glomerulosclerosis are found by light microscopy (Baumal et al., 1991).

Control: Males with signs of renal disease should be tested for the causative mutation. As it is an X-linked trait, the dam of affected males is an obligate carrier. Male siblings of affected dogs should be free of the mutation, but female siblings should be tested. Breeding of affected or carrier dogs is not recommended.

Genetic testing: There are tests available to detect the known causative mutations.

Breeds: Navasota (mixed breed), Samoyed.

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
COL4A5 collagen, type IV, alpha 5 Canis lupus familiaris X NC_051843.1 (83631540..83897969) COL4A5 Homologene, Ensembl, NCBI gene


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
Navasota (mixed breed) Nephritis, X-linked COL4A5 deletion, small (<=20) a 10 base pair deletion in exon 9 of COL4A5 2008 18931484
Samoyed Nephritis, X-linked COL4A5 nonsense (stop-gain) CanFam3.1 X g.82196868G>T c.3079G>T p.G1027* 1994 8171024 Variant coordinates obtained from or confirmed by EBI's Some Effect Predictor (VEP) tool


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.
2016 Clark, S.D., Nabity, M.B., Cianciolo, R.E., Dufek, B., Cosgrove, D. :
X-Linked Alport Dogs Demonstrate Mesangial Filopodial Invasion of the Capillary Tuft as an Early Event in Glomerular Damage. PLoS One 11:e0168343, 2016. Pubmed reference: 27959966. DOI: 10.1371/journal.pone.0168343.
2013 Lees, G.E. :
Kidney diseases caused by glomerular basement membrane type IV collagen defects in dogs. J Vet Emerg Crit Care (San Antonio) 23:184-93, 2013. Pubmed reference: 23464675. DOI: 10.1111/vec.12031.
2008 Bell, R.J., Lees, G.E., Murphy, K.E. :
X chromosome inactivation patterns in normal and X-linked hereditary nephropathy carrier dogs. Cytogenet Genome Res 122:37-40, 2008. Pubmed reference: 18931484. DOI: 10.1159/000151314.
2005 Rao, VH., Lees, GE., Kashtan, CE., Delimont, DC., Singh, R., Meehan, DT., Bhattacharya, G., Berridge, BR., Cosgrove, D. :
Dysregulation of renal MMP-3 and MMP-7 in canine X-linked Alport syndrome. Pediatr Nephrol 20:732-9, 2005. Pubmed reference: 15782307. DOI: 10.1007/s00467-004-1805-5.
Zheng, K., Perry, J., Harvey, SJ., Sado, Y., Ninomiya, Y., Jefferson, B., Jacobs, R., Hudson, BG., Thorner, PS. :
Regulation of collagen type IV genes is organ-specific: evidence from a canine model of Alport syndrome. Kidney Int 68:2121-30, 2005. Pubmed reference: 16221211. DOI: 10.1111/j.1523-1755.2005.00668.x.
2003 Chen, D., Jefferson, B., Harvey, S.J., Zheng, K., Gartley, C.J., Jacobs, R.M., Thorner, P.S. :
Cyclosporine a slows the progressive renal disease of alport syndrome (X-linked hereditary nephritis): results from a canine model Journal of the American Society of Nephrology 14:690-8, 2003. Pubmed reference: 12595505.
Cox, ML., Lees, GE., Kashtan, CE., Murphy, KE. :
Genetic cause of X-linked Alport syndrome in a family of domestic dogs. Mamm Genome 14:396-403, 2003. Pubmed reference: 12879362. DOI: 10.1007/s00335-002-2253-9.
Harvey, S.J., Zheng, K., Jefferson, B., Moak, P., Sado, Y., Naito, I., Ninomiya, Y., Jacobs, R., Thorner, P.S. :
Transfer of the alpha 5(IV) collagen chain gene to smooth muscle restores in vivo expression of the alpha 6(IV) collagen chain in a canine model of Alport syndrome American Journal of Pathology 162:873-85, 2003. Pubmed reference: 12598321.
2001 Harvey, S.J., Mount, R., Sado, Y., Naito, I., Ninomiya, Y., Harrison, R., Jefferson, B., Jacobs, R., Thorner, P.S. :
The inner ear of dogs with X-linked nephritis provides clues to the pathogenesis of hearing loss in X-linked Alport syndrome American Journal of Pathology 159:1097-1104, 2001. Pubmed reference: 11549602. DOI: 10.1016/S0002-9440(10)61785-3.
1999 Lees, G.E., Helman, R.G., Kashtan, C.E., Michael, A.F., Homco, L.D., Millichamp, N.J., Camacho, Z.T., Templeton, J.W., Ninomiya, Y., Sado, Y., Naito, I., Kim, Y. :
New form of X-linked dominant hereditary nephritis in dogs American Journal of Veterinary Research 60:373-383, 1999. Pubmed reference: 10188823.
1997 Grodecki, K.M., Gains, M.J., Baumal, R., Osmond, D.H., Cotter, B., Valli, V.E.O., Jacobs, R.M. :
Treatment of X-linked hereditary nephritis in Samoyed dogs with angiotensin converting enzyme (ACE) inhibitor Journal of Comparative Pathology 117:209-225, 1997. Pubmed reference: 9447482.
Lees, G.E., Wilson, P.D., Helman, R.G., Homco, L.D., Frey, M.S. :
Glomerular ultrastructural findings similar to hereditary nephritis in 4 English Cocker Spaniels Journal of Veterinary Internal Medicine 11:80-85, 1997. Pubmed reference: 9127294.
1996 Thorner, P.S., Zheng, K.Q., Kalluri, R., Jacobs, R., Hudson, B.G. :
Coordinate gene expression of the alpha-3, alpha-4, and alpha-5 chains of collagen type iv - evidence from a canine model of x-linked nephritis with a COL4A5 gene mutation Journal of Biological Chemistry 271:13821-13828, 1996. Pubmed reference: 8662866.
1994 Zheng, K.Q., Thorner, P.S., Marrano, P., Baumal, R., Mcinnes, R.R. :
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 Proceedings of the National Academy of Sciences of the United States of America 91:3989-3993, 1994. Pubmed reference: 8171024.
1992 Thorner, P.S., Baumal, R., Valli, V.E.O., Mahuran, D., Marrano, P.M., Jacobs, R. :
Production of Anti-NC1 Antibody by Affected Male Dogs with X- Linked Hereditary Nephritis - A Probe for Assessing the NC1 Domain of Collagen Type-IV in Dogs and Humans with Hereditary Nephritis Virchows Archiv A - Pathological Anatomy and Histopathology 421:467-475, 1992.
1991 Baumal, R., Thorner, P., Valli, V.E.O., Mcinnes, R., Marrano, P., Jacobs, R., Binnington, A., Bloedow, A.G. :
Renal Disease in Carrier Female Dogs with X-Linked Hereditary Nephritis - Implications for Female Patients with This Disease American Journal of Pathology 139:751-764, 1991. Pubmed reference: 1928300.
Valli, V.E.O., Baumal, R., Thorner, P., Jacobs, R., Marrano, P., Davies, C., Qizilbash, B., Clarke, H. :
Dietary Modification Reduces Splitting of Glomerular Basement Membranes and Delays Death Due to Renal Failure in Canine X- Linked Hereditary Nephritis Laboratory Investigation 65:67-73, 1991. Pubmed reference: 2072666.
1988 Thorner, P.S., Jansen, B., Baumal, R., Harrison, R.V., Mount, R.J., Valli, V.E., Spicer, P.M., Marrano, P.M. :
An immunohistochemical and electron microscopic study of extra-renal basement membranes in dogs with Samoyed hereditary glomerulopathy. Virchows Arch A Pathol Anat Histopathol 412:281-90, 1988. Pubmed reference: 3124348.
1987 Jansen, B.S., Valli, V.E., Thorner, P.S., Baumal, R. :
Scanning electron microscopy of cellular and acellular glomeruli of male dogs affected with Samoyed hereditary glomerulopathy and a carrier female. Can J Vet Res 51:475-80, 1987. Pubmed reference: 3453267.
Jansen, B., Valli, V.E., Thorner, P., Baumal, R., Lumsden, J.H. :
Samoyed hereditary glomerulopathy: serial, clinical and laboratory (urine, serum biochemistry and hematology) studies. Can J Vet Res 51:387-93, 1987. Pubmed reference: 3651895.
Thorner, P.S., Jansen, B., Liang, J., Baumal, R., Valli, V. :
Quantitation of anionic sites in glomerular capillary basement membranes of Samoyed dogs with hereditary glomerulopathy. Virchows Arch A Pathol Anat Histopathol 411:79-85, 1987. Pubmed reference: 2437692.
Thorner, P., Jansen, B., Baumal, R., Valli, V.E., Goldberger, A. :
Samoyed hereditary glomerulopathy. Immunohistochemical staining of basement membranes of kidney for laminin, collagen type IV, fibronectin, and Goodpasture antigen, and correlation with electron microscopy of glomerular capillary basement membranes. Lab Invest 56:435-43, 1987. Pubmed reference: 3550289.
1986 Jansen, B., Thorner, P., Baumal, R., Valli, V., Maxie, MG., Singh, A. :
Samoyed hereditary glomerulopathy (SHG). Evolution of splitting of glomerular capillary basement membranes. Am J Pathol 125:536-45, 1986. Pubmed reference: 4028523.
Jansen, B., Tryphonas, L., Wong, J., Thorner, P., Maxie, MG., Valli, VE., Baumal, R., Basrur, PK. :
Mode of inheritance of Samoyed hereditary glomerulopathy: an animal model for hereditary nephritis in humans. J Lab Clin Med 107:551-5, 1986. Pubmed reference: 3711721.
1984 Jansen, B., Thorner, P.S., Singh, A., Patterson, J.M., Lumsden, J.H., Valli, V.E., Baumal, R., Basrur, R.K. :
Animal model of human disease: hereditary nephritis in Samoyed dogs. Am J Pathol 116:175-8, 1984. Pubmed reference: 6742105.
1981 Bloedow, A.G. :
Familial renal disease in Samoyed dogs Veterinary Record 108:167-168, 1981. Pubmed reference: 7210449.
1977 Bernard, M.A., Valli, V.E. :
Familial renal disease in Samoyed dogs. Can Vet J 18:181-9, 1977. Pubmed reference: 884645.

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