A model of autosomal recessive Alport syndrome in English cocker spaniel dogs

A model of autosomal recessive Alport syndrome in English cocker spaniel dogs. Dogs with naturally occurring genetic disorders of basement membrane (type IV) collagen may serve as animal models of Alport syndrome. An autosomal recessive form of progressive hereditary nephritis (HN) was studied in 10 affected, 3 obligate carrier, and 4 unaffected English cocker spaniel (ECS) dogs. Clinical, pathological, and ultrastructural features of the disease were characterized. Expression of basement membrane (BM) proteins was examined with an immunohistochemical technique using monospecific antibodies. Affected dogs had proteinuria and juvenile-onset chronic renal failure. Glomerular basement membrane (GBM) thickening and multilamellation typical of HN were observed in all renal specimens obtained from proteinuric dogs, and severity of GBM ultrastructural abnormalities varied with the clinical stage of disease. Expression of α3(IV) and α4(IV) chains was totally absent in the kidney of affected dogs. Expression of α5(IV) and α6(IV) chains was normal in Bowman's capsule, collecting tubular BM and epidermal BM of affected dogs. The α5(IV) chain was not expressed in distal tubular BM of affected dogs. Expression of α5(IV) chains was markedly reduced but not absent, and expression of α6(IV) chains was present in GBM of affected dogs. Expression of α1-α2(IV) chains in GBM of affected dogs was increased. Features of obligate carriers were similar to those of unaffected dogs. We conclude that HN in ECS dogs is a naturally occurring animal model of autosomal recessive Alport syndrome. However, it differs from human disease in the persistence of α5(IV) chains in GBM and in the appearance of α6(IV) chains in GBM.