Hereditary systemic amyloidosis due to Asp76Asn variant β2-microglobulin.

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Valleix, Sophie | Gillmore, Julian D | Bridoux, Franck | Mangione, Palma P | Dogan, Ahmet | Nedelec, Brigitte | Boimard, Mathieu | Touchard, Guy | Goujon, Jean-Michel | Lacombe, Corinne | Lozeron, Pierre | Adams, David | Lacroix, Catherine | Maisonobe, Thierry | Planté-Bordeneuve, Violaine | Vrana, Julie A | Theis, Jason D | Giorgetti, Sofia | Porcari, Riccardo | Ricagno, Stefano | Bolognesi, Martino | Stoppini, Monica | Delpech, Marc | Pepys, Mark B | Hawkins, Philip N | Bellotti, Vittorio

Edité par CCSD ; Massachusetts Medical Society -

International audience. 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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