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Gene expression profile in hereditary transthyretin amyloidosis: differences in targeted and source organs
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.
Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
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2014 (English)In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, Vol. 21, no 2, 113-119 p.Article in journal (Refereed) Published
Abstract [en]

Introduction: Hereditary transthyretin amyloidosis (ATTR) is a genetic disease caused by a point mutation in the TTR gene that causes the liver to produce an unstable TTR protein. The most effective treatment has been liver transplantation in order to replace the variant TTR producing liver with one that produces only wild-type TTR. ATTR amyloidosis patients' livers are reused for liver sick patients, i.e. the Domino procedure. However, recent findings have demonstrated that ATTR amyloidosis can develop in the recipients within 7-8 years. The aim of this study was to elucidate how the genetic profile of the liver is affected by the disease, and how amyloid deposits affect target tissue. Methods: Gene expression analysis was used to unravel the genetic profiles of Swedish ATTR V30M patients and controls. Biopsies from adipose tissue and liver were examined. Results and Conclusions: ATTR amyloid patients' gene expression profile of the main source organ, the liver, differed markedly from that of the controls, whereas the target organs' gene expression profiles were not markedly altered in the ATTR amyloid patients compared to those of the controls. An impaired ER/protein folding pathway might suggest ER overload due to mutated TTR protein.

Place, publisher, year, edition, pages
2014. Vol. 21, no 2, 113-119 p.
Keyword [en]
Adipose tissue, familial amyloidosis, liver tissue, PCA, Simca, V30M
National Category
Medical Genetics
URN: urn:nbn:se:umu:diva-90410DOI: 10.3109/13506129.2014.894908ISI: 000336146700007OAI: diva2:733567

Originally included in thesis in manuscript form.

Available from: 2014-07-10 Created: 2014-06-23 Last updated: 2014-07-10Bibliographically approved
In thesis
1. 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.
Umeå University medical dissertations, ISSN 0346-6612 ; 1622
Hereditary transthyretin amyloidosis, Familial amyloid polyneuropathy, transthyretin, genealogy, founder effect, miRNA, allele-specific expression, gene expression, liver
National Category
Medical Genetics
Research subject
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)
Available from: 2014-01-10 Created: 2014-01-08 Last updated: 2014-07-10Bibliographically approved

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Norgren, NinaOlsson, MalinNyström, HannaSuhr, Ole B.
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