抄録
Familial amyloidotic polyneuropathy (FAP) is an autosomal dominant genetic disease, characterized by the extracellular deposition of amyloid fibrils and by prominent peripheral nerve involvement. The amyloid fibrils derived from FAP consist of variant transthyretin (TTR) with single amino acid substitutions. We demonstrated that the main cause of the Japanese FAP is the presence of a point mutation in the ttr gene. To investigate the molecular basis of FAP, we constructed transgenic mice carrying the human mutant ttr gene. In the transgenic mice, human TTR was deposited as amyloid fibrils in various tissues. Thus the transgenic mouse model of FAP can be used to elucidate the mechanism of amyloid deposition in FAP.
These transgenic mice, however, do not develop peripheral neuropathy. TTR is a serum protein which is involved in the transport of thyroid hormones and retinol. TTR is synthesized in the choroid plexus of brain and the retina of eye as well as in the liver. These observations suggest that TTR may play important roles in the nervous system. To elucidate the physiological function of TTR and the etiology of peripheral neuropathy in FAP, we have generated a unique strain of mice carrying a null mutation at the ttr locus by gene targeting.
Unexpectedly, the TTR-deficient mice are phenotypically normal. However, the levels of serum retinol, retinol-binding protein, and thyroid hormone (T4I) are significantly depressed in the mutant animals. These observations provide evidence that TTR is a major plasma carrier of retinol and T4I in mice. The TTR-deficient mice will be useful for investigating the transport and metabolism of retinoid and thyroid hormones.
In an attempt to generate a mouse model of FAP homozygous for the mutant ttr gene and to elucidate the function of the human variant TTR, we introduced the human mutant ttr gene into the TTR-deficient mice. In the TTR-deficient mice carrying the human mutant ttr gene, amyloid began to deposit at the age of 11 months. They appear to develop amyloid deposition earlier than wild type mice carrying the human mutant ttr gene.
