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Abstract
Familial transthyretin amyloidosis (ATTR) is a fatal autosomal dominant disease characterized by the formation of amyloid fibers, mainly composed of transthyretin (TTR). Protein aggregation and amyloid fiber formation are considered concentration dependent processes and since most ATTR patients are heterozygous it is crucial to determine the ratio between mutant and non-mutant TTR forms in human plasma. Using a high resolution mass spectrometry based approach we determined the ratio of TTR forms in ATTR patients, V30M mutation carriers, symptomatic and asymptomatic ones, as well as ATTR patients that received a wild type cadaveric liver transplant. Domino transplanted patients that received a liver from an ATTR patient were also investigated. We found that although wild type TTR is diminished in the plasma of non-transplanted ATTR patients comparatively to healthy subjects, the relationship with the V30M variant does not change with illness progression. Those who received a wild type liver showed no mutant protein while domino transplanted patients presented the same relative amount of V30M as found in asymptomatic and symptomatic individuals. The V30M to wild type TTR ratio in plasma is the same for all ATTR patients studied, showing no variation with disease clinical progression. Our results point to the involvement of additional non-genetic factors on the pathogenesis of this disease.
Acknowledgements
The authors wish to acknowledge Nurse Margarida for her outstanding cooperation in this work.
Declaration of interest: Work funded by Fundação para a Ciência e a Tecnologia do Ministério da Ciência Tecnologia e Ensino Superior, Portugal, for the Instrument Network Grant REDE/1501/REM/2005, Centro de Química e Bioquímica plurianual funding QUI-LVT-612 and grants PDTC/QUI/70610/2006 and SFRH/BPD/41037/2007.