Gene analysis of Japanese patients with familial amyloidotic polyneuropathy type IV]

Familial amyloidotic polyneuropathy type IV (FAP IV) is clinically characterized by slowly progressive cranial neuropathy and corneal lattice dystrophy. More than 300 cases were clustered in the Finnish population. Recent biochemical studies have demonstrated that the amyloid fibril protein in FAP IV is related to Asn-187 variant gelsolin, and the corresponding missense mutation, a G to A substitution at nucleotide 654 of plasma gelsolin cDNA, cosegregates with the disease phenotype in Finnish families. Here we analyzed the gelsolin gene of the Japanese family with FAP IV which we described as the first Japanese case. Direct sequence analysis of PCR-amplified DNA fragments spanning the codon 187 of plasma gelsolin cDNA from the 2 affected family members demonstrated a single base substitution, G to A at nucleotide 654, which is identical to the mutation of Finnish FAP IV. Restriction analysis using a modified PCR revealed that three unaffected family members and three unrelated healthy controls were homozygous for the normal allele, whereas the seven affected family members were heterozygous for the normal and the mutated alleles. This indicates the cosegregation of the mutation with the disease phenotype in this Japanese family, suggesting that the mutation causes the FAP IV phenotype regardless of ethnic background.