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Variation in amount of wild-type transthyretin in different fibril and tissue types in ATTR amyloidosis
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. (Forskargrupp Per Westermark)
Department of Internal Medicine, Umeå University, 901 85, Umeå, Sweden.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. (Forskargrupp Per Westermark)
2011 (English)In: Journal of Molecular Medicine, ISSN 0946-2716, E-ISSN 1432-1440, Vol. 89, no 2, 171-180 p.Article in journal (Refereed) Published
Abstract [en]

Familial transthyretin (TTR) amyloidosis is caused by a mutation in the TTR gene, although wild-type (wt) TTR is also incorporated into the amyloid fibrils. Liver transplantation (LT) is the prevailing treatment of the disease and is performed in order to eliminate the mutant TTR from plasma. The outcome of the procedure is varied; especially problematic is a progressive cardiomyopathy seen in some patients, presumably caused by continued incorporation of wtTTR. What determines the discrepancy in outcome is not clear. We have previously shown that two structurally distinct amyloid fibrils (with or without fragmented ATTR) are found among ATTRV30M patients. In this study, we investigated the proportion of wtATTR in cardiac and adipose amyloid from patients having either fibril type. It was found that cardiac amyloid more easily incorporates wtTTR than adipose amyloid, offering a potential explanation for the vulnerability of cardiac tissue for continued amyloidosis after LT. In cardiac tissue, fibrils with fragmented ATTR contained a higher wt proportion than fibrils without, suggesting that continued incorporation of wtTTR after LT, perhaps, can take place more easily in these patients. In adipose tissue, a rapid increase in wt proportion after LT indicates that a rather fast turnover of the deposits must occur. A difference in wt proportion between the fibril types was seen post-LT but not pre-LT, possibly caused by differences in turnover rate. Conclusively, this study further establishes the basic dissimilarities between the two fibril types and demonstrates that their role in LT outcome needs to be further investigated.

Place, publisher, year, edition, pages
2011. Vol. 89, no 2, 171-180 p.
Keyword [en]
Amyloid, Transthyretin, Familial amyloidotic polyneuropathy, Liver transplantation, Wild-type
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-150732DOI: 10.1007/s00109-010-0695-1ISI: 000288363300008PubMedID: 21107516OAI: oai:DiVA.org:uu-150732DiVA: diva2:408529
Available from: 2011-04-05 Created: 2011-04-05 Last updated: 2012-01-03Bibliographically approved
In thesis
1. Two Types of Fibrils in ATTR Amyloidosis: Implications for Clinical Phenotype and Treatment Outcome
Open this publication in new window or tab >>Two Types of Fibrils in ATTR Amyloidosis: Implications for Clinical Phenotype and Treatment Outcome
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Systemic amyloidoses are a group of lethal diseases where proteins aggregate into fibrillar structures, called amyloid fibrils, that deposits throughout the body. Transthyretin (TTR) causes one type of amyloidosis, in which the aggregates mainly infiltrate nervous and cardiac tissue. Almost a hundred different mutations in the TTR gene are known to trigger the disease, but wild-type (wt) TTR is also incorporated into the fibrils, and may alone form amyloid. Patients with the TTRV30M mutation show, for unknown reasons, two clinical phenotypes. Some have an early onset of disease without cardiomyopathy while others have a late onset and cardiomyopathy. It has previously been described that amyloid fibrils formed from TTRV30M can have two different compositions; either with truncated molecules beside full-length TTR (type A) or only-full-length molecules (type B).  In this thesis, the clinical importance of the two types of amyloid fibrils was investigated.

We found that the fibril composition types are correlated to the two clinical phenotypes seen among TTRV30M patients, with type A fibrils present in late onset patients and type B fibrils in early onset patients.

The only treatment for hereditary TTR amyloidosis has been liver transplantation, whereby the liver producing the mutant TTR is replaced by an organ only producing wt protein. However, in some patients, cardiac symptoms progress post-transplantationally. We demonstrated that the propensity to incorporate wtTTR differs between fibril types and tissue types in TTRV30M patients, with cardiac amyloid of type A having the highest tendency. This offers an explanation to why particularly cardiac amyloidosis develops after transplantation, and suggests which patients that are at risk for such development.

By examining patients with other mutations than TTRV30M, we showed that, in contrast to the general belief, a fibril composition with truncated TTR is very common and might even be the general rule. This may explain why TTRV30M patients often have a better outcome after liver transplantation than patients with other mutations.

In conclusion, this thesis has contributed with one piece to the puzzle of understanding the differences in clinical phenotype and treatment response between TTR amyloidosis patients, by demonstrating corresponding differences at a molecular level.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2011. 65 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 727
amyloid, transthyretin, familial amyloidotic polyneuropathy, TTRV30M, non-TTRV30M, wild-type, liver transplantation, cardiomyopathy, fibril composition
National Category
Biochemistry and Molecular Biology Cell and Molecular Biology Other Basic Medicine Clinical Laboratory Medicine
Research subject
Biochemistry; Biology with specialization in Molecular Biology; Experimental Pathology; Medical Biochemistry; Molecular Biology; Pathology
urn:nbn:se:uu:diva-160980 (URN)978-91-554-8234-3 (ISBN)
Public defence
2012-01-13, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjöldsv 20, Uppsala, 13:13 (Swedish)
Available from: 2011-12-20 Created: 2011-11-03 Last updated: 2012-01-03Bibliographically approved

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