title: Linkage of protection against amyloid fibril formation in the mouse to a single, autosomal dominant gene.
abstract: Inbred strains of mice provide a model for studies of the pathogenesis of amyloid A (AA) amyloidosis. All susceptible strains of mice described to date codominantly express two serum amyloid A (apoSAA) isoforms, apoSAA1 and apoSAA2, of which only apoSAA2 serves as a precursor for amyloid fibrils. In previous studies, we have shown that the CE/J strain, which produces a single, novel apoSAA isoform, apoSAACE/J, is amyloid resistant. In the present study amyloid-resistant CE/J females were mated with amyloid-susceptible CBA/J males to produce F1 hybrid offspring which were then backcrossed to the parental CBA/J mouse strain. Amyloid susceptibility was determined in 30 backcrossed mice 72 h after injection of murine amyloid enhancing factor and silver nitrate. ApoSAA isoforms in plasma were separated by isoelectric focusing gel electrophoresis and visualized after immunoblotting with anti-AA antiserum. Amyloid A fibrils in spleen homogenates were denatured by formic acid and AA protein was quantified by ELISA using anti-mouse apoSAA antibodies. Values < 5 apoSAA equivalent units were considered negative. 13 mice expressed an apoSAA1 and apoSAA2 doublet characteristic of CBA/J mice, whereas 17 mice, expressed the apoSAACE/J isoform codominantly with apoSAA1 and apoSAA2. The correlation of amyloid resistance to expression of the apoSAACE/J isoform was absolute (17/17 were negative; mean score 2.6 +/- 0.17 [standard error of the mean] apoSAA equivalent units) and the correlation between amyloid susceptibility and the expression of apoSAA2/apoSAA1 was also striking (12/13 were amyloid positive; mean score 47.9 +/- 9.0 [standard error of the mean] apoSAA equivalent units (P < 0.001). This is not significantly different from the 50% segregation of apoSAA phenotypes expected for linkage to a single gene. These results indicate that a single gene governs apoSAACE/J expression and thus confers protection against amyloid deposition even in the presence of apoSAA1 and apoSAA2 isoforms and show for the first time that resistance to AA amyloidosis is a dominant trait governed by a single gene.
authors.affiliation: E. N. Rogers Memorial Veterans Affairs Hospital, Bedford, Massachusetts 01730, USA.
authors.forename: W A
authors.initials: WA
authors.lastname: Gonnerman
authors.forename: R
authors.initials: R
authors.lastname: Elliott-Bryant
authors.forename: I
authors.initials: I
authors.lastname: Carreras
authors.forename: J D
authors.initials: JD
authors.lastname: Sipe
authors.forename: E S
authors.initials: ES
authors.lastname: Cathcart
mesh_terms: D000595:Amino Acid Sequence; D000686:Amyloidosis / Q000235:genetics*; D000818:Animals; D003433:Crosses, Genetic; D005260:Female; D015870:Gene Expression; D005799:Genes, Dominant; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA / Q000235:genetics; D008815:Mice, Inbred Strains / Q000235:genetics*; D008969:Molecular Sequence Data; D000685:Serum Amyloid A Protein / Q000096:biosynthesis / Q000235:genetics*; D013045:Species Specificity
chemical_list: D000685:Serum Amyloid A Protein