Journal
NEW ENGLAND JOURNAL OF MEDICINE
Volume 366, Issue 24, Pages 2276-2283Publisher
MASSACHUSETTS MEDICAL SOC
DOI: 10.1056/nejmoa1201356
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Funding
- U.K. National Health Service
- University College London
- U.K. Medical Research Council [G7900510, MR/K000187/1]
- Wolfson Foundation
- Cariplo Foundation [2009-2543]
- Italian Ministry of University and Research [FIRB RBFR109EOS, PRIN 20083ERXWS]
- MRC [G7900510, MR/K000187/1] Funding Source: UKRI
- Medical Research Council [G7900510, MR/K000187/1] Funding Source: researchfish
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We describe a kindred with slowly progressive gastrointestinal symptoms and autonomic neuropathy caused by autosomal dominant, hereditary systemic amyloidosis. The amyloid consists of Asp76Asn variant beta(2)-microglobulin. Unlike patients with dialysis-related amyloidosis caused by sustained high plasma concentrations of wild-type beta(2)-microglobulin, the affected members of this kindred had normal renal function and normal circulating beta 2-microglobulin values. The Asp76Asn beta(2)-microglobulin variant was thermodynamically unstable and remarkably fibrillogenic in vitro under physiological conditions. Previous studies of beta(2)-microglobulin aggregation have not shown such amyloidogenicity for single-residue substitutions. Comprehensive biophysical characterization of the beta(2)-microglobulin variant, including its 1.40-angstrom, three-dimensional structure, should allow further elucidation of fibrillogenesis and protein misfolding.
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