Identification of a novel transthyretin variant (Val³⁰→Leu) associated with familial amyloidotic polyneuropathy

Abstract

A novel variant transthyretin which contains a leucine‐for‐valine substitution at position 30 was isolated and identified in the serum of a patient with familial amyloidotic polyneuropathy (FAP). The amino acid substitution was proven to result from a guanine‐to‐cytosine change at the first base of codon 30 located in exon 2 in the mutated transthyretin gene by restriction fragment length analysis on the amplified transthyretin gene using Cfr13 I. The study indicates that the point mutation of the transthyretin gene is a cause of the disorder.

Familial amyloid polyneuropathy related to transthyretin mutation VaL30 to Leu in a Japanese family

“…1B). As has been reported previously, 4,6 this point mutation creates a restriction endonuclease site for Cfr13I (Fig. 1C).…”

“…4,6 This last mutation (Leu-for-Val), however, was observed only in a single case and could not be confirmed in other family members because there was no family history suggestive of FAP. 4,6 We now have identified this mutation in 3 members of a Japanese type 1 FAP family, showing for the first time a direct link between the mutation and the inheritance of type 1 FAP.…”

“…5 Val30 is located at the beginning of one ␤-strand, being placed into the subunit core located between two ␤-sheets. 6 The only previously reported case with the Leu30 TTR gene was also born in Iwate Prefecture, and then lived in Shizuoka Prefecture, in eastern Japan. [4][5][6] A blood relationship between this case and the present family, however, could neither be confirmed nor ruled out.…”

Transthyretin and Familial Amyloidotic Polyneuropathy.

“…Furthermore, owing to the progress of molecular genetics, various other types of FAP with different positions of amino acid substitution in TTR have been reported (5)(6)(7).…”

Diagnosis of familial amyloid polyneuropathy: wide-ranged clinicopathological features

“…Southern blot DNA analysis also became available in the same year [38]. Since the introduction of polymerase chain reaction for the allele-specific enzymatic amplification of genomic DNA, restriction fragment length analysis and DNA sequencing can be carried out more rapidly and easily, which has made it possible to identify the various mutations of the TTR gene related to the development of FAP [39]. Although DNA sequencing is at present the most common technique, the application of mass spectrometry or isoelectric focusing is also useful to identify the variant form of TTR [40][41][42].…”