A Basic Transthyretin Variant (GLU 61→LYS) Causes Familial Amyloidotic Polyneuropathy: Protein and DNA Sequencing and PCR-Induced Mutation Restriction Analysis

A new mutation of transthyretin (TTR) has been identified in a patient with late-onset familial amyloidotic polyneuropathy (FAP) of Japanese origin. Peptide mapping by reverse-phase high performance liquid chromatography to compare the patient′s TTR with normal TTR showed the presence of an abnormal peptide. Amino acid sequence analysis of the peptide (residues 49-61) showed a lysine-for-glutamic acid substitution at position 61. This substitution, verified by direct DNA sequencing, was the result of a guanine to adenine change on exon 3 of the TTR gene. A polymerase chain reaction-induced mutation restriction analysis (PCR-IMRA) system was established to rapidly detect the missense mutation. TTR-Lys 61 is the first variant TTR with a replacement of the acidic with basic amino acid to be found in the amyloid precursor proteins of FAP.