Germ Line Origin and Somatic Mutations Determine the Target Tissues in Systemic AL-Amyloidosis
- Uppsala University (Sweden); DOE/OSTI
- University of Oslo (Norway)
- Argonne National Laboratory (ANL), Argonne, IL (United States)
- Ludwig Institute for Cancer Research, Uppsala (Sweden)
- Uppsala University (Sweden)
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 Alzheimers 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 ALamyloidosis 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. 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 ALamyloid derived from the L2-L16 gene. Although the interindividual variations were pronounced, liver and kidney involvement was much more evident in the latter four. 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.
- Research Organization:
- Argonne National Laboratory (ANL), Argonne, IL (United States)
- Sponsoring Organization:
- USDOE Office of Science (SC), Biological and Environmental Research (BER); Research Council of Norway; Swedish Research Council; European Union
- Grant/Contract Number:
- AC02-06CH11357
- OSTI ID:
- 1627336
- Journal Information:
- PLoS ONE, Journal Name: PLoS ONE Journal Issue: 10 Vol. 2; ISSN 1932-6203
- Publisher:
- Public Library of ScienceCopyright Statement
- Country of Publication:
- United States
- Language:
- English
Similar Records
Structural Insights into the Role of Mutations in Amyloidogenesis
Immunoglobulin light chains, glycosaminoglycans and amyloid.