Haplotypes and DNA sequence variation within and surrounding the transthyretin gene: genotype–phenotype correlations in familial amyloid polyneuropathy (V30M) in Portugal and Sweden

Abstract

Familial amyloid polyneuropathy (FAP) is a lethal autosomal dominant disorder in which fibrils derived from mutant forms of transthyretin (TTR), the normal plasma carrier of thyroxine (T(4)) and retinol-binding protein, are deposited in tissues. Over 80 TTR sequence variants are associated with FAP, but the amino-acid substitutions alone do not completely explain the variability in disease penetrance, pathology and clinical course. To analyze the factors possibly contributing to this phenotypic variability, we characterized the variations within the wild-type and mutant (Val30Met) TTR genes and their flanking sequences by performing extended microsatellite haplotype analyses, sequencing and single-nucleotide polymorphism haplotyping of genomic DNA from Portuguese and Swedish carriers of V30M. We identified 10 new polymorphisms in the TTR untranslated regions, eight resulting from single-base substitutions and two arising from insertion/deletions in dinucleotide repeat sequences. The data suggest that the onset of symptoms of FAP V30M may be modulated by an interval downstream of TTR on the accompanying noncarrier chromosome (defined by microsatellites D18S457 and D18S456), but not by the immediately 5'- and 3'-flanking sequences of TTR. During the course of these studies, we also encountered the first instance in which the previously described intragenic haplotype III may be associated with V30M FAP in the Portuguese population.

Complement C1Q polymorphisms modulate onset in familial amyloidotic polyneuropathy TTR Val30Met

“…None of these polymorphisms appear to alter the phenotype appreciably. A study on a Portuguese and Swedish cohort analyzing variations within and surrounding the wild type and mutated TTR genes indicated that disease onset may be modulated by an interval downstream of TTR on the accompanying non carrier chromosome [29].…”

Genetic variation of the transthyretin gene in wild-type transthyretin amyloidosis (ATTRwt)

“…For example, ATTRm due to the p.V50M (V30M) substitution has a much earlier onset in patients from endemic areas of Portugal and Japan, compared to Sweden where onset generally occurs later in life (Zaros et al 2008). It has recently been suggested that non-coding variants in cis-regulatory regions may impact expression of the TTR gene in ATTRm (Soares et al 2004; Olsson et al 2010; Polimanti et al 2013); this cis-regulatory hypothesis is offered as an explanation for varying levels of penetrance, age at onset, disease severity, and sex differences, possibly correlating with serum TTR levels (Buxbaum et al 2008; Buxbaum et al 2010). One recent study investigating genetic variation in non-coding regions of the TTR gene implicated a haplotype containing upstream and downstream single nucleotide polymorphisms (SNPs) as a potential modulator of early disease onset in the Portuguese V30M ATTRm amyloidosis population (Soares et al 2004), where disease development occurs in the 3 rd and 4 th decades of life.…”

“…It has recently been suggested that non-coding variants in cis-regulatory regions may impact expression of the TTR gene in ATTRm (Soares et al 2004; Olsson et al 2010; Polimanti et al 2013); this cis-regulatory hypothesis is offered as an explanation for varying levels of penetrance, age at onset, disease severity, and sex differences, possibly correlating with serum TTR levels (Buxbaum et al 2008; Buxbaum et al 2010). One recent study investigating genetic variation in non-coding regions of the TTR gene implicated a haplotype containing upstream and downstream single nucleotide polymorphisms (SNPs) as a potential modulator of early disease onset in the Portuguese V30M ATTRm amyloidosis population (Soares et al 2004), where disease development occurs in the 3 rd and 4 th decades of life. A later study found the T allele of SNP rs62093482 to be associated with Swedish V30M ATTRm amyloidosis (Olsson et al 2010), where disease onset is usually reported after age 60; this SNP was located in a predicted miRNA binding site.…”

Intracavernous Trigeminal Ganglion Amyloidoma

“…Amyloid is an amorphous and heterogenous protein deposit associated with a variety of inflammatory and noninflammatory conditions, such as plasmacytomas, chronic renal failure, rheumatoid arthritis, and familial transthyretin mutations (25,31,40,45,49,55). In rare instances, amyloidomas, consisting of β-pleated proteins with variable amounts of N-terminal digestion, may arise in the absence of any obvious sources of exuberant protein production (14,30,51).…”