Familial amyloid polyneuropathy in Taiwan: Identification of transthyretin variant (Leu⁵⁵ → Pro)

Abstract

We report a family with familial amyloid polyneuropathy (FAP), showing an early-onset and a fatal outcome before age 30. Transthyretin (TTR) gene analysis showed one point mutation (T-->C change) in the second base of codon 55, and the corresponding amino acid substitution of proline (Pro) for leucine (Leu) was confirmed at the protein level. This is the first FAP family of Taiwanese origin demonstrating a causative gene abnormality, and FAP with TTR-Pro55 was considered to be more serious compared with other forms of FAP.

Evidence for Early Cytotoxic Aggregates in Transgenic Mice for Human Transthyretin Leu55Pro

“…4,5 Under normal physiological conditions, TTR, a homotetrameric plasma protein, 6 functions as the carrier for both thyroxine (T4) and retinol (vitamin A); in the latter case through binding to retinol-binding protein. TTR is mainly synthesized by the liver and the choroid plexuses of the brain and in lesser amounts by the retina of the eye, pancreas, and other tissues.…”

Familial amyloidosis in one Chinese family: clinical, immunological, and molecular genetic analysis

“…This mechanism is unlikely allele creates a new restriction site for the enzyme AciI ; thus, the TTR Pro 55 variant can be detected simply and specifically by PCR of a DNA segment spanning TTR exon 3 followed by AciI digestion, as demonstrated here. In previous reports, the mutant allele has been confirmed by PCR-primer introduced restriction analysis (PCR-PIRA), where a PCR primer containing a mismatch from the target DNA was used to create a new BstUI restriction site [5] or a new SplI site [4]. The present test is preferable because it does not require the use of a specially designed mismatched primer.…”

“…Digestion of the TTR exon 2 PCR product with NsiI, which detects the most common amyloidogenic TTR variant, TTR Met 30 [4], revealed a normal digestion pattern. AluI digestion of the exon 3 PCR product, which normally contains an AluI site in codons 54 and 55, revealed that the proband was heterozygous for a digestion-resistant allele, indicating a mutation in the last two bases of codon 54 or the first two bases of codon 55 (not shown).…”

“…We have studied three siblings in a Taiwanese family with documented systemic amyloidosis. Some information on this family has been previously reported [4]. We now present additional clinical details, a complete family tree, immunogenetic studies, the results of echocardiographic testing, and abdominal pain, vomiting, corneal ulcerations, cardiomyopathy, and syncope.…”

“…Similarly, familial amyloid syndromes have rarely been reported in Taiwan Chinese [1,2]. To date, only two reports of Taiwanese families with familial amyloidosis have appeared [3,4]. We have studied three siblings in a Taiwanese family with documented systemic amyloidosis.…”