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      Segregation of Experimental Autoimmune Glomerulonephritis as a Complex Genetic Trait and Exclusion of Col4a3 as a Candidate Gene

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          Experimental autoimmune glomerulonephritis (EAG), an animal model of Goodpasture’s disease, can be induced in Wistar-Kyoto (WKY) rats (RT1-l) by immunization with rat glomerular basement membrane (GBM) in adjuvant. The model in this rat strain is characterized by anti-GBM antibody production accompanied by focal necrotizing glomerulonephritis with crescent formation. The main autoantigen in humans and rats has been identified as the non-collagenous domain of the α3 chain of type IV collagen (α3(IV)NC1). By contrast, Lewis (LEW) rats with the same MHC background (RT1-l), immunized with the same antigen, develop similar levels of circulating anti-GBM antibodies, but no histological evidence of nephritis. In order to investigate the genetic basis of susceptibility to EAG, we examined the response of both F1 (WKY × LEW) and backcross (BC1; WKY × F1) rats to immunization with rat GBM. F1 animals were completely resistant to the development of EAG, while BC1 animals showed a range of responses from severe crescentic glomerulonephritis to no histological evidence of disease. The results indicate that EAG is inherited as a complex trait under the control of WKY genes unlinked to the MHC. cDNA sequence analysis of α3(IV)NC1 in the two parental strains was identical, indicating no predicted amino acid sequence variation in the α3(IV)NC1 domain between these strains. Radiation hybrid mapping, using two separate PCR amplicons from rat α3(IV)NC1, localized rat Col4a3 to a region of chromosome 9. Since Col4a3 (encoding the autoantigen) is a candidate for susceptibility to EAG, we screened the region of rat chromosome 9 where Col4a3 is localized, using polymorphic microsatellite markers in segregating BC1 progeny. No significant linkage was detected. These results exclude Col4a3 as a recessive susceptibility gene for EAG in the BC1 progeny.

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          Identification of Cd36 (Fat) as an insulin-resistance gene causing defective fatty acid and glucose metabolism in hypertensive rats.

          The human insulin-resistance syndromes, type 2 diabetes, obesity, combined hyperlipidaemia and essential hypertension, are complex disorders whose genetic basis is unknown. The spontaneously hypertensive rat (SHR) is insulin resistant and a model of these human syndromes. Quantitative trait loci (QTLs) for SHR defects in glucose and fatty acid metabolism, hypertriglyceridaemia and hypertension map to a single locus on rat chromosome 4. Here we combine use of cDNA microarrays, congenic mapping and radiation hybrid (RH) mapping to identify a defective SHR gene, Cd36 (also known as Fat, as it encodes fatty acid translocase), at the peak of linkage to these QTLs. SHR Cd36 cDNA contains multiple sequence variants, caused by unequal genomic recombination of a duplicated ancestral gene. The encoded protein product is undetectable in SHR adipocyte plasma membrane. Transgenic mice overexpressing Cd36 have reduced blood lipids. We conclude that Cd36 deficiency underlies insulin resistance, defective fatty acid metabolism and hypertriglyceridaemia in SHR and may be important in the pathogenesis of human insulin-resistance syndromes.
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            A genetic linkage map of the laboratory rat, Rattus norvegicus.

            We report the construction of the first complete genetic linkage map of the laboratory rat. By testing 1171 simple sequence length polymorphisms (SSLPs), we have identified 432 markers that show polymorphisms between the SHR and BN rat strains and mapped them in a single (SHR x BN) F2 intercross. The loci define 21 large linkage groups corresponding to the 21 rat chromosomes, together with a pair of nearby markers on chromosome 9 that are not linked to the rest of the map. Because 99.5% of the markers fall into one of the 21 large linkage groups, the maps appear to cover the vast majority of the rat genome. The availability of the map should facilitate whole genome scans for genes underlying qualitative and quantitative traits relevant to mammalian physiology and pathobiology.
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              Construction of a detailed physical and transcript map of the candidate region for Russell-Silver syndrome on chromosome 17q23-q24.

              Russell-Silver syndrome (RSS) is a heterogeneous disorder characterized mainly by pre- and postnatal growth retardation and characteristic dysmorphic features. The genetic cause of this syndrome is unknown. However, two autosomal translocations involving chromosome 17q25 were reported in association with RSS. Molecular analysis of the breakpoint on chromosome 17 of the de novo translocation previously described as t(1;17)(q31;q25) enabled us to refine the localization of the chromosome 17 breakpoint to 17q23-q24. Since no detailed mapping data were available for this region, we established a contig of yeast artificial chromosomes, P1 artificial chromosomes, bacterial artificial chromosomes, and cosmid clones for a 17q segment flanked by the sequence-tagged site (STS) markers D17S1557 and D17S940. This contig covers a physical distance of 4-5 Mb encompassing several novel markers. A transcript map was constructed by assigning genes and expressed sequence tags to the clone contig, and altogether 74 STS markers were mapped. Furthermore, the locus order and content provide insight into several duplication events that have occurred in the chromosomal region 17q23-q24. On the basis of our refined map, we have reduced the translocation breakpoint region to 65 kb between the newly derived markers 58T7 and CF20b. These data provide the molecular tools for the final identification of the RSS gene in 17q23-q24. Copyright 2001 Academic Press.

                Author and article information

                Nephron Exp Nephrol
                Cardiorenal Medicine
                S. Karger AG
                09 October 2002
                : 10
                : 5-6
                : 402-407
                aRenal Section, Division of Medicine and bMolecular Medicine Group, MRC Clinical Sciences Centre and Imperial College Genetics and Genomics Research Institute, Imperial College, Hammersmith Hospital, London, UK
                65297 Exp Nephrol 2002;10:402–407
                © 2002 S. Karger AG, Basel

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                Page count
                Figures: 2, References: 22, Pages: 6
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/65297
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