Transgenic Mouse Model of an Autosomal Dominant Disease: Familial Amyloidotic Polyneuropathy
Familial amyloidotic polyneuropathy (FAP) is an autosomal dominant disorder characterized by the extracellular deposition of amyloid fibrils and by prominent peripheral nerve involvement (Andrade 1952). The first symptoms usually appear in individuals between 20 and 45 years of age, and the disease is always progressive and fatal in about 10 to 20 years. The amyloid protein is mainly composed of transthyretin (TTR; a protein formerly known as prealbumin) with a substitution of methionine for valine at position 30 in the FAP type I, as reported in Japan, Sweden, and Portugal (Tawara et al. 1983; Saraiva et al. 1984; Dwulet et al. 1984). These amyloid deposits also contain a small but significant amount of serum amyloid P component (SAP) (Skinner et al. 1982). Several other different amino acid substitutions have been identified in different areas (Benson 1989). These amino acid substitutions are thought to lead to amyloid deposition. The human TTR gene has been cloned and well characterized at molecular level (Tsuzuki et al. 1985; Sasaki et al. 1985). Using this gene it is now possible to carry out a DNA diagnosis of FAP. All the Japanese FAP patients so far examined are heterozygotes, carrying one normal and mutant gene (Sasaki et al. 1984; Mita et al. 1986; Ide et al. 1986). Thus, it is clear that the main cause of this disease is the presence of a mutant TTR gene. However, in patients with FAP, the age at onset varies from 20s to 45 years. In addition the clinical syndrome is variable even among kindreds with the same genetic defect. These data suggest involvement of factor(s) other than the single nucleotide mutation in the TTR gene. Furthermore, there is no specific therapy for FAP. To elucidate the pathological process of this disease development and to devise a new method for treatment, we have attempted to produce a transgenic mouse model of FAP.
KeywordsNeuropathy Methionine Fibril Hematoxylin Valine
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