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A Model of Autosomal Recessive Alport Syndrome in English Cocker Spaniel Dogs

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A Model of Autosomal Recessive Alport Syndrome in English Cocker Spaniel Dogs View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Kidney International, Vol. 54 (1998), pp. 706–719 A model of autosomal recessive Alport syndrome in English cocker spaniel dogs GEORGE E. LEES,R.GAYMAN HELMAN,CLIFFORD E. KASHTAN,ALFRED F. MICHAEL,LINDA D. HOMCO, NICHOLAS J. MILLICHAMP,YOSHIFUMI NINOMIYA,YOSHIKAZU SADO,ICHIRO NAITO, and YOUNGKI KIM Texas Veterinary Medical Center, Texas A&M University, College Station, Texas, Oklahoma Animal Disease Diagnostic Laboratory, Oklahoma State University, Stillwater, Oklahoma, and Department of Pediatrics, University of Minnesota Medical School, Minneapolis, Minnesota, USA; Department of Molecular Biology and Biochemistry, Okayama University Medical School, Okayama, and Divisions of Immunology and Ultrastructural Biology, Shigei Medical Research Institute, Okayama, Japan A model of autosomal recessive Alport syndrome in English cause progressive glomerular disease [1–3]. In humans with cocker spaniel dogs. Alport syndrome (AS), the nephropathy is frequently asso- Background. Dogs with naturally occurring genetic disorders of basement membrane (type IV) collagen may serve as animal ciated with sensorineural hearing loss and ocular abnormal- models of Alport syndrome. ities. Distinctive ultrastructural changes in glomerular base- Methods. An autosomal recessive form of progressive heredi- ment membranes (GBM) of affected individuals is a tary nephritis (HN) was studied in 10 affected, 3 obligate carrier, prominent characteristic of these disorders [1–3]. and 4 unaffected English cocker spaniel (ECS) dogs. Clinical, In humans AS usually is X-linked, resulting from muta- pathological, and ultrastructural features of the disease were a characterized. Expression of basement membrane (BM) proteins tions in the COL4A5 gene, which encodes the 5 chain of was examined with an immunohistochemical technique using type IV collagen [1, 4]. Some families have an autosomal monospecific antibodies. recessive form of AS, due to mutations in the COL4A3 or Results. Affected dogs had proteinuria and juvenile-onset COL4A4 gene on chromosome 2, that affect the a3(IV) or chronic renal failure. Glomerular basement membrane (GBM) a thickening and multilamellation typical of HN were observed in 4(IV) chain [5–8]. Rare families have AS with an auto- all renal specimens obtained from proteinuric dogs, and severity somal dominant pattern of inheritance [9]. Jefferson et al of GBM ultrastructural abnormalities varied with the clinical have mapped autosomal dominant AS to the region of a a stage of disease. Expression of 3(IV) and 4(IV) chains was COL4A3 and COL4A4 in a single family, but have yet to totally absent in the kidney of affected dogs. Expression of a5(IV) and a6(IV) chains was normal in Bowman’s capsule, collecting identify a specific mutation [10]. tubular BM and epidermal BM of affected dogs. The a5(IV) Naturally occurring diseases that are animal models for chain was not expressed in distal tubular BM of affected dogs. AS have been identified in dogs. An X-linked form of HN Expression of a5(IV) chains was markedly reduced but not a in a family of Samoyed dogs has been thoroughly charac- absent, and expression of 6(IV) chains was present in GBM of terized [11–16]. The causative mutation, located in exon 35 affected dogs. Expression of a1-a2(IV) chains in GBM of affected dogs was increased. Features of obligate carriers were similar to of the COL4A5 gene, is a single nucleotide substitution those of unaffected dogs. that produces a premature stop codon [17]. Additionally, Conclusions. We conclude that HN in ECS dogs is a naturally autosomal dominant HN has been described in bull terrier occurring animal model of autosomal recessive Alport syndrome. dogs, but the causative mutation is unknown [18]. However, it differs from human disease in the persistence of a5(IV) chains in GBM and in the appearance of a6(IV) chains in We have identified an autosomal recessive form of HN in GBM. English cocker spaniel (ECS) dogs. Initially, ultrastructural GBM lesions similar to those of HN were identified in several juvenile ECS dogs that had advanced renal failure Hereditary nephritis (HN) refers to a group of genetic [19]. Subsequently, repeated matings of the parents of disorders of basement membrane (type IV) collagen that affected dogs produced additional affected dogs [20]. Oc- currence of an inherited nephropathy in ECS dogs has been Key words: genetic disorder, chronic renal failure, hereditary nephritis, recognized for many years; however, previous investigators basement membrane, type IV collagen, progressive glomerular disease, multilamination. had not clearly established that the disease was a form of HN [21–25]. Nonetheless, studies had shown that the Received for publication August 11, 1997 and in revised form April 6, 1998 disease was a rapidly progressive glomerular disorder that Accepted for publication April 14, 1998 was inherited in an autosomal recessive fashion [26, 27]. © 1998 by the International Society of Nephrology Pedigrees of affected ECS dogs that we studied also were 706 Lees et al: Autosomal recessive Alport syndrome in dogs 707 Table 1. English cocker spaniel dogs studied Age at Age at initial last exam exam TEM HN Renal thick Dog no. Family phenotype Gender months Proteinuria failure GBM 1 A Affected M 10 11 Pos Pos Pos 2 B Affected M — 27 Pos Pos Pos 3 C Affected M 15 22 Pos Pos Pos 4 D Affected F — 13 Pos Pos Pos 5 E Affected M 9 9 Pos Pos Pos 6 F Affected M — 10 Pos Pos Pos 7 G Affected F — 15 Pos Pos Pos 8 A Affected M 3 8 Pos Pos Pos 9 H Affected F 3 13 Pos Pos Pos 10 H Affected F 3 17 Pos Pos Pos 11 A Carrier M — 88 Neg Neg ND 12 A Carrier F 59 73 Neg Neg Neg 13 I Carrier F 102 104 Neg Neg Neg 14 H Unaffected M 3 50 Neg Neg Neg 15 J Normal M — 19 Neg Neg Neg 16 K Normal F — 76 Neg Neg Neg 17 L Normal F — 9 Neg Neg Neg Dogs 1 and 8 were siblings but not littermates; dogs 11 and 12 were parents of dogs 1 and 8. Dogs 9, 10, and 14 were littermate siblings. Abbreviations are: HN, hereditary nephritis; TEM, transmission electron microscopy; Affected, HN diagnosis based on clinicopathologic features and TEM findings; Carrier, parent of an HN-affected dog; Unaffected, healthy dog from HN-carrier parents; could be a carrier or a normal dog; Normal, kindred contains no HN-affected dogs, and little chance of being a HN-carrier; ND, not determined. compatible with autosomal recessive transmission of the mine the distribution of a(IV) chains in renal and epider- disease [20]. mal basement membranes of affected dogs. Immunohistochemical techniques have been used to study distribution of collagen a(IV) chains in basement METHODS membranes of humans with AS, dogs with HN, and trans- a genic mice with COL4A3 mutations. Expression of 3(IV), Dogs a4(IV), and a5(IV) usually is absent in the GBM of men with X-linked AS, while women who are heterozygous for Subjects were 17 ECS dogs that were selected in several X-linked AS mutations frequently lack these chains in ways (Table 1). Seven dogs (numbers 1 to 7) were identified portions of their GBM [28–31]. In people with autosomal when they developed juvenile-onset chronic renal failure. recessive AS, a3(IV), a4(IV), and a5(IV) chains usually As described in a previous clinical report, which included are lacking in GBM; however, the a5(IV) chain is present four of these animals, such dogs were found be HN- in other basement membranes, for example, Bowman’s affected by postmortem examinations that revealed char- capsule, collecting tubular basement membrane, and epi- acteristic ultrastructural GBM changes [19]. Four dogs dermal basement membrane [32]. Transgenic COL4A3 (numbers 8 to 10, and 14) were offspring from repeat mutant mice lack a3(IV), a4(IV) and a5(IV) chains in matings of dogs that had produced an affected dog in a their GBM and tubular basement membranes [33, 34]. previous litter. Three of these four dogs also were affected Human sera from patients with Goodpasture disease have [20]. Three dogs (numbers 11 to 13) were obligate HN been used to study X-linked HN in Samoyed dogs. These carriers, identified by having at least one offspring in which sera, which contain antibodies reacting mainly with a3(IV) HN had been diagnosed. Three dogs (numbers 15 to 17) chains, bind to normal dog GBM but not to the GBM of were healthy animals that served as controls. affected males [14]. Segmental GBM staining is seen in Each affected dog met two criteria for diagnosis of HN. young heterozygous females, but staining becomes global as First, the kidney disease exhibited clinicopathologic fea- the dogs grow older [16]. In bull terrier dogs with autoso- tures identical to those described for the familial nephrop- mal dominant HN, renal expression of a3(IV) and a5(IV) athy that has been recognized in ECS dogs for many years. chains appeared normal using monospecific antibodies Second, examination with transmission electron micros- [18]. copy (TEM) demonstrated characteristic abnormalities of This article describes the clinical, ultrastructural and GBM ultrastructure. Every dog with the clinicopathologic immunohistochemical features of autosomal recessive HN features of familial nephropathy that was examined with in ECS dogs. Monospecific antibodies were used to deter- TEM had similar GBM changes. 708 Lees et al: Autosomal recessive Alport syndrome in dogs Clinical evaluations Table 2. Primary antibodies used in immunohistochemical studies Reference or Eight dogs were evaluated once, and nine dogs were Name Type Specificity source evaluated on 2 to 26 occasions. Five dogs with multiple MAb M3F7 Monoclonal a1/a2(IV) helix [38] evaluations were examined two to six times at irregular MAb 102 Monoclonal a1(IV) NC1 [39] intervals.
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