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Germ Line Origin and Somatic Mutations Determine the Target Tissues in Systemic AL-Amyloidosis
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 am...
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Formato: | Texto |
Lenguaje: | English |
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Public Library of Science
2007
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1989140/ https://www.ncbi.nlm.nih.gov/pubmed/17912358 http://dx.doi.org/10.1371/journal.pone.0000981 |
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author | Enqvist, Stina Sletten, Knut Stevens, Fred J. Hellman, Ulf Westermark, Per |
author_facet | Enqvist, Stina Sletten, Knut Stevens, Fred J. Hellman, Ulf Westermark, Per |
author_sort | Enqvist, Stina |
collection | PubMed |
description | 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. |
format | Text |
id | pubmed-1989140 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2007 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-19891402007-10-03 Germ Line Origin and Somatic Mutations Determine the Target Tissues in Systemic AL-Amyloidosis Enqvist, Stina Sletten, Knut Stevens, Fred J. Hellman, Ulf Westermark, Per PLoS One Research Article 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. Public Library of Science 2007-10-03 /pmc/articles/PMC1989140/ /pubmed/17912358 http://dx.doi.org/10.1371/journal.pone.0000981 Text en Enqvist et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Enqvist, Stina Sletten, Knut Stevens, Fred J. Hellman, Ulf Westermark, Per Germ Line Origin and Somatic Mutations Determine the Target Tissues in Systemic AL-Amyloidosis |
title | Germ Line Origin and Somatic Mutations Determine the Target Tissues in Systemic AL-Amyloidosis |
title_full | Germ Line Origin and Somatic Mutations Determine the Target Tissues in Systemic AL-Amyloidosis |
title_fullStr | Germ Line Origin and Somatic Mutations Determine the Target Tissues in Systemic AL-Amyloidosis |
title_full_unstemmed | Germ Line Origin and Somatic Mutations Determine the Target Tissues in Systemic AL-Amyloidosis |
title_short | Germ Line Origin and Somatic Mutations Determine the Target Tissues in Systemic AL-Amyloidosis |
title_sort | germ line origin and somatic mutations determine the target tissues in systemic al-amyloidosis |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1989140/ https://www.ncbi.nlm.nih.gov/pubmed/17912358 http://dx.doi.org/10.1371/journal.pone.0000981 |
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