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Familial amyloidosis with polyneuropathy: studies of genetic factors modifying the phenotype of the disease
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
2010 (English)Doctoral thesis, comprehensive summary (Other academic)Alternative title
Familjär amyloidos med polyneuropati : studier av genetiska faktorer som modifierar sjukdomsfeneotypen (Swedish)
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 [en]
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: urn:nbn:se:umu:diva-34128ISBN: 978-91-7459-005-0 (print)OAI: oai:DiVA.org:umu-34128DiVA: diva2:319071
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
List of papers
1. Frequency of the transthyretin Val30Met mutation in the northern Swedish population
Open this publication in new window or tab >>Frequency of the transthyretin Val30Met mutation in the northern Swedish population
2014 (English)In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, Vol. 21, no 1, 18-20 p.Article in journal (Other academic) Published
Abstract [en]

By genotyping a large number of samples from the Northern Sweden Health and Disease Study cohort, a carrier frequency could be determined for the Skelleftea and Lycksele populations. A previous study of the amyloidogenic transthyretin mutation TTRV30M in Northern Sweden's endemic area has shown a large variation in carrier frequency and penetrance of the trait within the area. However, the estimations have been based on a small sample size within the different regions in the area and therefore, the wide variation in TTRV30M carrier frequency observed between the Lycksele and Skelleftea populations are uncertain. Based on a total of 3460 samples, the estimated overall carrier frequency in the two regions was 1.82% with a carrier frequency in the Skelleftea and Lycksele population of 1.63% and 2.02%, respectively. Thus, the previously reported extremely high frequency in the Lycksele region compared to that of the Skelleftea region could not be substantiated. However, it does not change the previous finding of a surprisingly higher carrier frequency in the population from endemic area of Northern Sweden compared to that reported from endemic areas in Portugal.

Keyword
amyloidosis-hereditary-neuropathic, ATTRV30M (p.ATTRV50M), frequency, genotyping, mutation, transthyretin, TTR c.(Val50Met)
National Category
Medical Genetics
Research subject
Genetics
Identifiers
urn:nbn:se:umu:diva-34124 (URN)10.3109/13506129.2013.860027 (DOI)000335764200003 ()
Note

Originally published in dissertation in manuscript form.

Available from: 2010-05-12 Created: 2010-05-12 Last updated: 2014-06-18Bibliographically approved
2. Mitochondrial haplogroup is associated with the phenotype of familial amyloidosis with polyneuropathy in Swedish and French patients
Open this publication in new window or tab >>Mitochondrial haplogroup is associated with the phenotype of familial amyloidosis with polyneuropathy in Swedish and French patients
Show others...
2009 (English)In: Clinical Genetics, ISSN 0009-9163, E-ISSN 1399-0004, Vol. 75, no 2, 163-168 p.Article in journal (Refereed) Published
Abstract [en]

Familial amyloidotic polyneuropathy (FAP) is a monogenic disease caused by mutations in the transthyretin (TTR) gene. The phenotype of the most common TTR mutation, V30M, varies within and between populations. Oxidative stress and protein misfolding are cellular processes involved in the development of FAP. Because the mitochondria are important for both these processes, we investigated if mitochondrial haplogroups are related to age at onset of the disease in Swedish and French FAP patients. Mitochondrial haplogroup analysis was performed on 25 early-onset (below 40 years) and 29 late-onset (above 51 years) Swedish FAP patients. DNA from 249 Swedish individuals served as controls. In addition, 6 early-onset and 17 late-onset French FAP patients were examined with 25 French controls. The haplogroup distribution among late-onset Swedish and French cases was similar to that found in the general populations, whereas among early-onset cases a different haplogroup distribution was seen. The relatively rare haplogroup K was significantly more common among early-onset cases. Our findings substantiate the suggestion that a genetic component, still to be found, affecting mitochondrial function has an impact on the amyloid generating process in transthyretin amyloidosis.

National Category
Medical Genetics
Research subject
Genetics
Identifiers
urn:nbn:se:umu:diva-22119 (URN)10.1111/j.1399-0004.2008.01097.x (DOI)19018796 (PubMedID)
Available from: 2009-04-23 Created: 2009-04-23 Last updated: 2012-08-10Bibliographically approved
3. Distribution of mitochondrial DNA haplogroups in Portuguese familial amyloidosis with polyneuropathy (FAP) patients
Open this publication in new window or tab >>Distribution of mitochondrial DNA haplogroups in Portuguese familial amyloidosis with polyneuropathy (FAP) patients
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(English)Manuscript (preprint) (Other academic)
Keyword
Amyloidosis-hereditary-neuropathic; mitochondrial haplogroup; transthyretin
National Category
Medical Genetics
Research subject
Genetics
Identifiers
urn:nbn:se:umu:diva-34125 (URN)
Available from: 2010-05-12 Created: 2010-05-12 Last updated: 2010-05-18Bibliographically approved
4. TTR familial amyloid polyneuropathy: does a mitochondrial polymorphism entirely explain the parent-of-origin difference in penetrance?
Open this publication in new window or tab >>TTR familial amyloid polyneuropathy: does a mitochondrial polymorphism entirely explain the parent-of-origin difference in penetrance?
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2010 (English)In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438Article in journal (Refereed) Published
Abstract [en]

The Val30Met transthyretin familial amyloid polyneuropathy (TTR-V30M-FAP) is the most frequent familial amyloidosis, with autosomal dominant transmission. This severe disease shows important differences in age of onset and penetrance. Recently, a difference in penetrance according to the gender of the transmitting parent was elicited in different geographic areas with a higher penetrance in case of maternal transmission of the trait. In addition, differences in mitochondrial haplogroup distribution in early and late onset Swedish and French cases of TTR-V30M-FAP suggested that a polymorphism of mitochondrial DNA could be one underlying mechanism of the phenotypic variation. We further investigated this hypothesis by modeling the penetrance function with a parent-of-origin and/or a mitochondrial polymorphism effect in samples of Portuguese (n=33) and Swedish families (n=86) with TTR-V30M-FAP in which several individuals had been tested for mitochondrial haplogroups. Our analysis showed that a mitochondrial polymorphism effect was sufficient to explain the observed difference in penetrance according to gender of the transmitting parent in the Portuguese sample, whereas, in the Swedish sample, a clear residual parent-of-origin effect remained. This study further supported the role of a mitochondrial polymorphism effect that might induce a higher penetrance in case of maternal inheritance of the disease. In clinical practice, these results might help to better delineate the individual disease risk and have a significant impact on the management of both patients and carriers.

Keyword
transthyretin amyloid polyneuropathy, parent-of-origin, mitochondria, penetrance
National Category
Medical Genetics
Research subject
Genetics
Identifiers
urn:nbn:se:umu:diva-34123 (URN)10.1038/ejhg.2010.36 (DOI)20234390 (PubMedID)
Note
E-pub ahead of printAvailable from: 2010-05-12 Created: 2010-05-12 Last updated: 2012-06-21Bibliographically approved
5. A possible role for miRNA silencing in disease phenotype variation in Swedish transthyretin V30M carriers
Open this publication in new window or tab >>A possible role for miRNA silencing in disease phenotype variation in Swedish transthyretin V30M carriers
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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.

Keyword
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:nbn:se:umu:diva-39677 (URN)10.1186/1471-2350-11-130 (DOI)000283195800001 ()20840742 (PubMedID)
Available from: 2011-02-03 Created: 2011-02-03 Last updated: 2017-12-11Bibliographically approved

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