AA amyloidosis-resistant CE/J mice haveSaa1andSaa2genes that encode an identical SAA isoform

Abstract

The CE/J mouse strain is resistant to Amyloid A protein (AA) amyloidosis. In contrast to AA amyloidosis-susceptible mouse strains that concomitantly express serum amyloid precursor protein (SAA) type 1 and 2 isoforms encoded by the Saa1 and Saa2 genes, respectively, in response to inflammatory stimulation from the liver, CE/J mice express only a single SAA isoform named SAA2.2. In addition, CE/J mice uniquely possess a Q30L amino acid substitution in SAA2.2 that inhibits amyloidogenesis. To elucidate the genetic basis underlying the expression of only a single SAA isoform in this strain, we conducted PCR cloning and nucleotide sequencing of the Saa1 and Saa2 genes from the CE/J genome. We revealed that CE/J mice possess functional Saa1 and Saa2 genes. Intriguingly, the 2 genes were identical with respect to amino acid sequence, each encoding the SAA2.2 isoform.RT-PCR analysis of inflamed liver tissue from CE/J mice demonstrated that both genes are expressed at equivalent levels. Reporter assays revealed that promoter/enhancer sequences of Saa1 and Saa2 genes in CE/J are also functional. These results indicate that the SAA2.2 isoform in CE/J is a mixture of Saa1 and Saa2 gene products.

AA Amyloidosis: Pathogenesis and Targeted Therapy

“…Murine SAA2.2 protein is an abnormal SAA protein from the mouse CE/J strain, which is highly resistant to AA amyloidosis. Significant genetic data suggest this resistance can be attributed to the presence of SAA2.2 and the absence of normal SAA1 protein (46,47). Although the pathogenic relevance of SAA2.2 oligomers remains to be established, oligomers from the disease-relevant SAA1 protein isoform have been associated with the induction of amyloidosis and the activity of amyloid-enhancing factor (AEF) (48).…”

Serum amyloid A – a review

“…Interestingly, Mori et al (2014) noted that CE/J mice with a Q30L substitution in both SAA1 and SAA2 are resistant to amyloidosis, presumably implicating a critical domain.…”

Serum amyloid A1: Structure, function and gene polymorphism

“…Mouse Saa1.1 as a mature protein has 103 amino acids and shares 76% sequence identity with the human counterpart (Figure 3). Mice predominantly expressing Saa1.1 and 2.1 are susceptible to AA amyloidosis, whereas mice expressing Saa2.2 (the CE/J mice) are resistant to AA amyloidosis (Mori et al, 2014), mainly due to its proline-rich cluster of 13 amino acids in the C-terminus (Patke et al, 2012). The two mouse Saa proteins share many properties with human acute-phase SAA (see comparison of human SAA1.1 and the mouse counterpart in Figure 3), and are therefore used often in in vivo studies.…”