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A possible role for miRNA silencing in disease phenotype variation in Swedish transthyretin V30M carriers
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
Department of Diagnostic Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Service de Neurologie, CHU Henri Mondor, Créteil, France.
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2010 (English)In: BMC Medical Genetics, ISSN 1471-2350, E-ISSN 1471-2350, Vol. 11, 130- p.Article in journal (Refereed) Published
Abstract [en]

Our results are the first to show the presence of a 3'UTR polymorphism on the V30M haplotype in Swedish carriers, which can serve as a miRNA binding site potentially leading to down-regulated expression from the mutated TTR allele. This finding may be related to the low penetrance and high age at onset of the disease observed in the Swedish patient population.

Place, publisher, year, edition, pages
2010. Vol. 11, 130- p.
Keyword [en]
Allele Frequency; Amyloidosis; Amyloid Neuropathies, Familial; Humans; MicroRNA; Polymorphism, Single Nucleotide; Transthyretin; 3' Untranslated Regions/genetics
National Category
Medical Genetics
Research subject
Genetics
Identifiers
URN: urn:nbn:se:umu:diva-39677DOI: 10.1186/1471-2350-11-130ISI: 000283195800001PubMedID: 20840742OAI: oai:DiVA.org:umu-39677DiVA: diva2:394687
Available from: 2011-02-03 Created: 2011-02-03 Last updated: 2017-12-11Bibliographically approved
In thesis
1. Familial amyloidosis with polyneuropathy: studies of genetic factors modifying the phenotype of the disease
Open this publication in new window or tab >>Familial amyloidosis with polyneuropathy: studies of genetic factors modifying the phenotype of the disease
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Familjär amyloidos med polyneuropati : studier av genetiska faktorer som modifierar sjukdomsfeneotypen
Abstract [en]

Background. Familial Amyloidosis with Polyneuropathy (FAP) is an autosomal dominantly inherited systemic amyloid disease. The disease is caused by mutations in the transthyretin (TTR) gene, where close to 100 different amyloidogenic mutations have been identified. FAP is found worldwide, but endemic areas with a high frequency of patients are found in Portugal, Japan and northern Sweden. Cases from these endemic areas all share the same TTR c.148G>A, p.V50M ("V30M") mutation, but the phenotype of the disease varies between the areas, and also within the endemic areas. The mean onset of the disease is two decades earlier in Portugal and Japan compared to Sweden, but late as well as early age at onset cases occur within all the populations. Interestingly, the different populations all display a maternal anticipation, where an earlier onset is observed for those individuals who inherit the trait from their mother. Since substantial variation in the phenotype is observed for different populations, epigenetic/genetic and/or environmental factors must exert a significant impact on the penetrance of the disease. Amyloid formation is caused by conformational changes of proteins, which facilitates their assembly into fibrils, amyloid. Oxidative stress can mediate conformational changes of proteins and since the mitochondria regulate oxidative processes within the cell, mitochondrial function may affect amyloid formation. The mitochondrial DNA is a non-nuclear DNA, which is entirely maternally inherited, and therefore could be related to the observed maternal anticipation of the disease. In addition, differences within the surrounding regions of the TTR gene may have an impact on the transcription of the gene and thereby on the expression of the different alleles.

Material and methods. DNA from early and late onset V30M cases and from non-carriers (the latter utilised as controls) from Swedish, French, Japanese and Portuguese populations were analysed. In addition, DNA from healthy Swedish V30M carriers was analysed. Conventional analytical methods were employed, such as PCR, sequencing and genotyping. Conventional statistical methods used were t-test, Chi-squared test and maximum likelihood.

Results. The study of V30M carrier frequency in two counties (Lycksele and Skellefteå) within the Swedish endemic area revealed a carrier frequency of 2.14% and 2.54%, respectively. The mitochondrial haplogroup analysis showed that in populations with generally late onset (French and Swedish), the haplogroup distribution of late onset cases resembled that of the controls derived from the same area, whereas haplogroup distribution for early onset patients was significantly different. The most pronounced difference was for the rare haplogroup K, of which early onset cases had a higher frequency than the controls. Analysis of the Portuguese population, with predominantly early onset, showed that haplogroup distribution for early onset cases were similar to the Portuguese control group, which had a different distribution than the Swedish control group. By analysis of pedigrees from Swedish and Portuguese patients it could be shown that mitochondrial genetic variation entirely could explain maternal anticipation in the Portuguese patients, whereas for Swedish patients, an additional parent of origin effect is present. Our analysis of the TTR gene disclosed a polymorphism (rs62093482) in the 3'UTR region of the Swedish patients. This polymorphism was found in all V30M carriers, irrespective of symptoms. In addition, homozygous TTR V30M carriers were homozygous also for the polymorphism. Since Swedish patients share a common founder this polymorphism thus is localised on the V30M allele. This polymorphism was found in only 4% of the Swedish controls. French controls showed the same frequency, but none of the French V30M patients displayed the polymorphism. In the Japanese population the polymorphism was not present at all. Interestingly, this polymorphism generates a potential binding site for microRNA and thereby possibly could down-regulate the expression of the mutated TTR allele.

Conclusions. The carrier frequency in the endemic area is remarkably high, above 2% in the Lycksele and Skellefteå areas. The prevailing haplogroup distributions in the different endemic areas are consistent between the general population and the patient group with the predominant phenotype of that area. Mitochondrial genetic differences may explain maternal anticipation in Portuguese patients, and have an influence in Swedish patients. A polymorphism in the 3'UTR regulatory region of the mutated TTR allele is found in all Swedish patients. This polymorphism may down-regulate TTR V30M expression and thereby contribute to the late onset of the disease noted in the Swedish population.

Place, publisher, year, edition, pages
Umeå: Umeå university, 2010. 49 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1351
Keyword
Familial amyloid polyneuropathy; Amyloidosis; Transthyretin; Allele Frequency, Mitochondria, parent-of-origin, MicroRNA, Single Nucleotide Polymorphism, 3' Untranslated Regions/genetics
National Category
Medical Genetics Medical Genetics
Research subject
Genetics; Clinical Genetics; Medicine
Identifiers
urn:nbn:se:umu:diva-34128 (URN)978-91-7459-005-0 (ISBN)
Public defence
2010-06-03, sal B, 9 trappor, NUS, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2010-05-14 Created: 2010-05-12 Last updated: 2011-02-05Bibliographically approved
2. Hereditary transthyretin amyloidosis (ATTR V30M): from genes to genealogy
Open this publication in new window or tab >>Hereditary transthyretin amyloidosis (ATTR V30M): from genes to genealogy
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Ärftlig transtyretinamyloidos (Skelleftesjukan) : från arvsanlag till släktträd
Abstract [en]

Background: Hereditary transthyretin amyloidosis is an autosomal dominant disease with a reduced penetrance. The most common mutation in Sweden is the V30M mutation in the transthyretin gene. Clustering areas of the disease can be found in Northern Sweden, Portugal, Brazil and Japan, although sporadic cases exist worldwide. Despite being caused by the same mutation, there are large differences in onset, penetrance and symptoms of the disease. Swedish V30M patients typically have a later onset with a lower penetrance compared to those from the clustering Portuguese V30M areas. The reasons for these differences have not been fully understood. The aim of this thesis is to study mechanisms that may influence onset and symptoms and investigate why patients carrying the same mutation have different phenotypes.

Methods: Genealogy studies were performed on all known V30M carriers in Sweden using standard genealogy methods. DNA samples from patients, asymptomatic carriers and controls from different countries were collected and the transthyretin gene was sequenced. Liver biopsies from patients were used for allele specific expression analysis and a cell assay was used for miRNA analysis with the mutated allele. Gene expression analysis was performed on biopsies from liver and fat from patients and controls.

Results and conclusions: Genealogic analysis of all known Swedish V30M carriers managed to link together 73% of the Swedish ATTR V30M population to six different ancestors from the 17th and 18th century, thus dating the Swedish V30M mutation to be more than 400 years old. A founder effect was also visible in descendants to one of the ancestors, producing a later age at onset. Sequencing of the transthyretin gene revealed a SNP in the 3’ UTR of all Swedish V30M carriers that was not found in any of the Japanese or French V30M carriers. The SNP was present on the Swedish transthyretin haplotype and defined the Swedish V30M population as separate from others. However, the SNP itself had no effect upon phenotype or onset of disease. Gene expression analysis of liver and fat tissue revealed a change in genetic profile of the patients’ livers, in contrast to the unchanged profile of the fat tissue. A changed genetic profile of the liver could explain why domino liver recipients develop the disease much earlier than expected.

Place, publisher, year, edition, pages
Umeå: Umeå Universitet, 2014. 49 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1622
Keyword
Hereditary transthyretin amyloidosis, Familial amyloid polyneuropathy, transthyretin, genealogy, founder effect, miRNA, allele-specific expression, gene expression, liver
National Category
Medical Genetics
Research subject
Medicine
Identifiers
urn:nbn:se:umu:diva-84494 (URN)978-91-7459-786-8 (ISBN)
Public defence
2014-01-31, Sal D, 9 trappor, byggnad 1D, Norrlands Universitetssjukhus, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2014-01-10 Created: 2014-01-08 Last updated: 2014-07-10Bibliographically approved

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