Bull terrier hereditary nephritis: A model for autosomal dominant Alport syndrome

Abstract

Bull terrier hereditary nephritis is inherited as an autosomal dominant disease and causes renal failure at variable ages in affected dogs. The aims of this study were to compare the clinical, ultrastructural and immunohistochemical features of bull terrier hereditary nephritis with the characteristics of the human forms of Alport syndrome. Many animals with bull terrier hereditary nephritis have hematuria, and some have anterior lenticonus. However, deafness is not associated with the renal disease, and affected dogs do not have the large platelets that are occasionally seen in patients with autosomal Alport syndrome. The glomerular capillary basement membrane (GCBM) in affected bull terriers has an identical ultrastructural appearance to that seen in X-linked Alport syndrome, with lamellations and intramembranous electron-dense deposits. However, both the Goodpasture and the Alport antigens, which represent parts of the alpha 3(IV) and alpha 5(IV) collagen chains, respectively, are present in the GCBM of affected dogs. Bull terrier hereditary nephritis represents an animal model for autosomal dominant Alport syndrome, and can be used to further examine how genetic mutations affect a basement membrane protein and the corresponding membrane structure.

Histologic and Ultrastructural Studies of Juvenile Onset Renal Disease in Four Rottweiler Dogs

“…The cystic glomerular capsular change, which was present in these Rottweilers, has been described in Bull Terriers 5,7 and some Doberman Pinschers 2 but has not been reported in people and other dog breeds with Alport syndrome. This lesion has been termed ''cystic glomerular atrophy,'' based on the small size of some glomeruli within the dilated Bowman's space.…”

“…15,17 Changes in the kidney described in these diseases include agenesis, hypoplasia, dysplasia, glomerulopathy, tubulointerstitial nephropathy, and tubular transport dysfunction. 17 Primary inherited glomerular basement membrane abnormalities have been described in the juvenile onset renal diseases of Samoyeds, 1,9 Doberman Pinschers, 2,18 English Cocker Spaniels, 12,13 Bull Terriers, 7,15 Dalmatian dogs, 6 and mixed breed ''Navasota'' dogs; 11 these diseases share similarities with Alport syndrome in people. 10 Alport syndrome is the result of congenital defect in the molecular structure of type IV collagen, which is the major structural component of the glomerular basement membrane (GBM).…”

“…Although there is variability in the light microscopic renal lesions among breeds of dogs and people with Alport syndrome, the GBM ultrastructural changes of lamellation are pathognomonic for this disease. 6,7,9,10,11,13,18 Therefore, a diagnosis of this disease is absolutely dependent on ultrastructural examination of the kidney. Further studies are needed to define the suspected collagen defect present in Rottweiler dogs with this juvenile onset renal disease.…”

Expert Guidelines for the Management of Alport Syndrome and Thin Basement Membrane Nephropathy

“…Autosomal recessive inheritance is confirmed when there are two COL4A3 or two COL4A4 pathogenic mutations or the GBM lacks the collagen IV a3, a4, and a5 chains but the a5 chain persists in the Bowman capsule and the distal tubular and the epidermal membrane. 21,61 Genetic Testing Genetic testing is useful to confirm the diagnosis of autosomal recessive Alport syndrome 16 when it is suspected on the basis of clinical features, family history, or renal immunohistochemistry. Fewer mutations have been described for recessive than for X-linked disease, and too few are known for genotype-phenotype correlations.…”

Glomerular Expression of Type IV Collagen Chains in Normal and X-Linked Alport Syndrome Kidneys

“…28 -31 The presence of cysteine-rich ␣3(IV) and ␣4(IV) chains, forming with ␣5(IV) a network containing loops and supercoiled triple helices stabilized by disulfide bonds between the chains, seems to be important with regards to the longterm stability of the GBM and its role as a filter. 26,32 Despite the increasing number of AS mutations reported in the literature [12][13][14][15][16][17][18][19] and the existence of AS animal models, [33][34][35][36][37] several questions regarding the consequences of AS mutations on the collagen organization within the GBM and the mechanisms responsible for the progressive development of AS nephropathy remain unanswered. A striking feature observed in the majority of AS is the absence of all three ␣3(IV), ␣4(IV), and ␣5(IV) chains within the GBM although only one of these chains is actually mutated.…”