Molecular genetic analysis of familial amyloidotic polyneuropathy

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Familial amyloidotic polyneuropathy (FAP) is an autosomal dominant disorder characterized by extracellular deposition of amyloid fibrils and by prominent peripheral and autonomic nerve involvement. Although the gene responsible for this disease has been identified as the transthyretin (TTR) gene and well characterized at molecular level, many questions, such as the mechanism of amyloid deposition, remain to be elucidated. We formerly produced two lines of transgenic mice by introducing the human mutant TTR gene containing its own promoter (0.6-hTTR30) or metallothionein promoter (MT-hTTR30). In these two lines the total serum concentrations of human mutant TTR were the same. However, the onset of amyloid deposition in MT-hTTR30 lines was 6 months of age and was 9 months earlier than that in the 0.6-hTTR30 lines. These results suggest that the concentration of homo-tetramers composed of human mutant TTR but not the total amount of human mutant TTR molecule is important for amyloid deposition.To analyze the role of the human serum amyloid P component (SAP) which is a minor component of amyloid fibrils, we also produced SAP transgenic mice. Interestingly, the serum levels of human SAP were roughly proportional to the number of copies integrated and were higher than that of the human serum in three lines. These mice were mated with MT-hTTR30 transgenic to obtain mice carrying both genes. In these mice the onset of amyloid deposition was not accelerated suggesting that human SAP is not involved in the initiation of amyloid deposition.Strangely enough, there were no amyloid deposits in peripheral nervous tissues where amyloid deposition is commonly observed in FAP patients. These results suggest that the production of mutant TTR molecule in the chorid plexus or high level expression is required for the amyloid deposition in these tissues.