Categories: Renal / urinary system phene

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

Links to MONDO diseases: No links.

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, X-linked hereditary nephropathy, glomerulonephritis, X- linked nephritis

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. For other types of hereditary nephritis see also: 'OMIA001359-9615 Nephritis, autosomal recessive'; 'OMIA001114-9615 Nephritis, autosomal dominant' ;OMIA000708-9615 Nephritis' and 'OMIA 000413-9615 Glomerulonephritis'.

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.

Possible clinical features may also include hearing loss (Harvey et al., 2001) and and anterior lenticonus (Kashtan, 2002). [IT thanks DVM student Muhammad Elsayed for contributions to this entry in April 2022]

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 (Baumal et al., 1991). The thinning and thickening of the glomerular basement membrane appears as “basket weave” patterns under electron microscopy (Clark et al., 2016). Areas of focal segmental glomerulosclerosis are found by light microscopy (Baumal et al., 1991).

These basement membrane changes are also indicated to cause decreased strength of the lens capsule preventing maintenance of normal lens shape (Kashtan, 2002). Alport syndrome also weakens the interaction between the extracellular matrix in the ear resulting in reduced tension on the basement membrane and an inability to respond to high frequency sounds (Harvey et al., 2001). [IT thanks DVM students Muhammad Elsayed and Ji Youn Lee for contributions to this entry in April 2022]

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: Cocker Spaniel, Navasota (mixed breed), Samoyed.

Associated gene: