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Germ Line Origin and Somatic Mutations Determine the Target Tissues in Systemic AL-Amyloidosis
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
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2007 (English)In: PLoS ONE, ISSN 1932-6203, Vol. 2, no 10, e981- p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Amyloid is insoluble aggregated proteins deposited in the extra cellular space. About 25 different proteins are known to form amyloid in vivo and are associated with severe diseases such as Alzheimeŕs disease, prion diseases and type-2 diabetes. Light chain (AL) -amyloidosis is unique among amyloid diseases in that the fibril protein, a monoclonal immunoglobulin light chain, varies between individuals and that no two AL-proteins with identical primary structures have been described to date. The variability in tissue distribution of amyloid deposits is considerably larger in systemic AL-amyloidosis than in any other form of amyloidosis. The reason for this variation is believed to be based on the differences in properties of the amyloidogenic immunoglobulin light chain. However, there is presently no known relationship between the structure of an AL-protein and tissue distribution. METHODOLOGY/PRINCIPAL FINDINGS: We compared the pattern of amyloid deposition in four individuals with amyloid protein derived from variable light chain gene O18-O8, the source of a high proportion of amyloidogenic light chains, and in whom all or most of the fibril protein had been determined by amino acid sequencing. In spite of great similarities between the structures of the proteins, there was a pronounced variability in deposition pattern. We also compared the tissue distribution in these four individuals with that of four other patients with AL-amyloid derived from the L2-L16 gene. Although the interindividual variations were pronounced, liver and kidney involvement was much more evident in the latter four. CONCLUSIONS/SIGNIFICANCE: We conclude that although the use of a specific gene influences the tissue distribution of amyloid, each light chain exhibits one or more determinants of organ-specificity, which originate from somatic mutations and post-translational modifications. Eventual identification of such determinants could lead to improved treatment of patients with AL amyloidosis.

Place, publisher, year, edition, pages
2007. Vol. 2, no 10, e981- p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-11975DOI: 10.1371/journal.pone.0000981ISI: 000207455900017PubMedID: 17912358OAI: oai:DiVA.org:uu-11975DiVA: diva2:39744
Available from: 2007-11-08 Created: 2007-11-08 Last updated: 2011-01-14Bibliographically approved
In thesis
1. Influence of Genes and Post-translational Modifications in the Pathogenesis of Light Chain Amyloidosis
Open this publication in new window or tab >>Influence of Genes and Post-translational Modifications in the Pathogenesis of Light Chain Amyloidosis
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Amyloid is formed when a normally soluble protein undergoes conformational changes that results in self-aggregation. The pathogenic protein in light chain amyloidosis is an immunoglobulin light chain produced by a plasma cell clone mainly in the bone marrow. The light chain is transported via the circulation to various organs and tissues but deposits only in certain locations. The disease is very heterogenous and every patient can be considered to have their own disease, since symptoms and outcome vary enormously. In this thesis I have tried to elucidate some factors involved in the pathogenesis of light chain amyloidosis.

Firstly, we investigated the impact of the germ line origin for tissue affinity and found out that even though it is important other factors like posttranslational modifications are also of relevance.

Secondly we describe familial-like light chain amyloidosis in Sweden, affecting a father and son. The inheritance is hard to explain but we believe that genetic factors that might be involved in the rearrangement of light chain genes or that familial immunopathies predispose certain families for development of light chain amyloidosis.

Thirdly, we wanted to study if cleavage of the light chain occurs before or after deposition, since purified light chain amyloid contains full-length, and N- and C-terminal fragments of the protein. The cleavage pattern in 1-5 organs from 6 patients was analyzed by Western blot with three antisera directed against one epitope in the N-terminal and two epitopes in the N- and C-terminal part of the protein. By using these antisera we could determine to which part of the light chain molecule the fragment belonged. We found fragments that could be aligned to compose the whole light chain. The finding indicates that cleavage occurs after deposition.

Finally, we wanted to investigate if lambda amyloid fibrils contain small C-terminal fragments from the constant domain, earlier been detected in patients with kappa light chain amyloidosis. In concordance, we identified the same fragments in lambda patients and could demonstrate that these fragments made fibrils in vitro. The role of the small C-terminal peptides for the development of light chain amyloidosis must be further investigated.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. 51 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 455
National Category
Medical and Health Sciences
Research subject
urn:nbn:se:uu:diva-100899 (URN)978-91-554-7514-7 (ISBN)
Public defence
2009-05-20, Fåhreussalen, Dag Hammarskjöldsväg 20 , Uppsala, 09:00 (English)
Available from: 2009-04-28 Created: 2009-04-10 Last updated: 2009-04-30Bibliographically approved

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Enqvist, StinaHellman, UlfWestermark, Per
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