| Budget Amount *help |
¥2,200,000 (Direct Cost: ¥2,200,000)
Fiscal Year 1994: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 1993: ¥1,400,000 (Direct Cost: ¥1,400,000)
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| Research Abstract |
Familial amyloidotic polyneuropathy (FAP) is an autosomal dominant inherited disorder characterized by progressive motor, sensory and autonomic polyneuropathy and by lethal cardiac and renal amyloidosis. Age of onset, progression of illness, genetic penetrance and main organ involvement considerably vary in subtypes of FAP.We have shown that the disease results from systemic deposition of amyloid fibril protein which consists of a variant transthyretin (TTR) with one amino acid substitution. We have found seven variant TTRs by amino acid sequence analysis in cooperation with many researchers in Japan and other countries. Their amino acid substitutions are Val^<30>*Met, Val^<30>*Leu, Phe^<33>*Ile, Thr^<60>*Ala, Glu^<61>*Lys, Ser^<77>*Tyr, and Ala^<97>*Gly. Point mutations in the TTR gene responsible for these substitutions were determined by direct DNA sequening. DNA diagnostic methods also were established by restriction fragment length polymorphism of amplified TTR exons or PCR-induced mutation restriction analysis. BIOCES analysis of the variant TTR molecules showed slight to drastic changes in their tertiary structure compared to the normal molecule, which may be related to mild to severe clinical manifestations in subtypes of FAP or to incomplete penetrance of clinical expression in some types of FAP.
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