Abstract
BackgroundHereditary transthyretin (TTR) amyloidosis (ATTR) is an autosomal dominant disease characterized by extracellular deposits of amyloid fibrils composed of misfolded TTR. The differences in penetrance and age at onset are vast, both between and within populations, with a generally late onset for Swedish carriers. In a recent study the entire TTR gene including the 3′ UTR in Swedish, French and Japanese ATTR patients was sequenced. The study disclosed a SNP in the V30M TTR 3′ UTR of the Swedish ATTR population that was not present in either the French or the Japanese populations (rs62093482-C>T). This SNP could create a new binding site for miRNA, which would increase degradation of the mutated TTR’s mRNA thus decrease variant TTR formation and thereby delay the onset of the disease. The aim of the present study was to disclose differences in allele specific TTR expression among Swedish V30M patients, and to see if selected miRNA had any effect upon the expression.Methodology/Principal FindingsAllele-specific expression was measured on nine liver biopsies from Swedish ATTR patients using SNaPshot Multiplex assay. Luciferase activity was measured on cell lines transfected with constructs containing the TTR 3′ UTR. Allele-specific expression measured on liver biopsies from Swedish ATTR patients showed no difference in expression between the two alleles. Neither was there any difference in expression between cell lines co-transfected with two constructs with or without the TTR 3′ UTR SNP regardless of added miRNA.Conclusions/SignificanceThe SNP found in the 3′ UTR of the TTR gene has no effect on degrading the variant allele’s expression and thus has no impact on the diminished penetrance of the trait in the Swedish population. However, the 3′ UTR SNP is unique for patients descending from the Swedish founder, and this SNP could be utilized to identify ATTR patients of Swedish descent.
Highlights
Hereditary transthyretin (TTR) amyloidosis (ATTR) is an autosomal dominant disease, where mutations in the TTR gene cause the normally stable tetrameric structure to dissociate into amyloigenic monomers that aggregate into fibrils in peripheral tissues
Results mRNA Levels of Patients Carrying the SNP rs62093482-T Showed Similar Transcriptional Expression Pattern between the Mutated and Wild Type Allele mRNA transcriptional expressions from the mutated and wild type allele were measured on nine liver biopsies from heterozygous Swedish V30M carriers
One of the samples was found to be homozygous for the rs62093482-T SNP but heterozygous for the V30M mutation and used as a negative control
Summary
Hereditary transthyretin (TTR) amyloidosis (ATTR) is an autosomal dominant disease, where mutations in the TTR gene cause the normally stable tetrameric structure to dissociate into amyloigenic monomers that aggregate into fibrils in peripheral tissues. [1] Clinical symptoms often consist of a peripheral sensorymotor neuropathy and/or hypertrophic cardiomyopathy. [2] The phenotypic variations between different mutations and individuals, as well as different populations, are vast. 5% of the Swedish and French V30M carriers will have developed symptomatic disease at the age of 40 compared with 56% for the Portuguese population. The explanation for these remarkable differences in the phenotypes has not been elucidated. The study disclosed a SNP in the V30M TTR 39 UTR of the Swedish ATTR population that was not present in either the French or the Japanese populations (rs62093482-C.T) This SNP could create a new binding site for miRNA, which would increase degradation of the mutated TTR’s mRNA decrease variant TTR formation and thereby delay the onset of the disease. The aim of the present study was to disclose differences in allele specific TTR expression among Swedish V30M patients, and to see if selected miRNA had any effect upon the expression
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