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Genetic Analysis of Hereditary Transthyretin Ala97Ser Related Amyloidosis
Published on: June 9, 2018
Hereditary systemic amyloidosis due to Asp76Asn variant β2-microglobulin
Sophie Valleix1, Julian D Gillmore, Frank Bridoux
1Laboratoire de Biochimie et de Génétique Moléculaire, Université Paris-Descartes, Sorbonne Paris Cité, Faculté de Médecine Paris, Assistance Public–Hôpitaux de Paris (AP-HP), Paris, France. sophie.valleix@cch.aphp.fr
Abstract:
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 β(2)-microglobulin. Unlike patients with dialysis-related amyloidosis caused by sustained high plasma concentrations of wild-type β(2)-microglobulin, the affected members of this kindred had normal renal function and normal circulating β(2)-microglobulin values. The Asp76Asn β(2)-microglobulin variant was thermodynamically unstable and remarkably fibrillogenic in vitro under physiological conditions. Previous studies of β(2)-microglobulin aggregation have not shown such amyloidogenicity for single-residue substitutions. Comprehensive biophysical characterization of the β(2)-microglobulin variant, including its 1.40-Å, three-dimensional structure, should allow further elucidation of fibrillogenesis and protein misfolding.
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