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.
Hereditary systemic amyloidosis due to Asp76Asn variant β2-microglobulin / S. Valleix, J.D. Gillmore, F. Bridoux, P.P. Mangione, A. Dogan, B. Nedelec, M. Boimard, G. Touchard, J.M. Goujon, C. Lacombe, P. Lozeron, D. Adams, C. Lacroix, T. Maisonobe, V. Planté-Bordeneuve, J.A. Vrana, J.D. Theis, S. Giorgetti, R. Porcari, S. Ricagno, M. Bolognesi, M. Stoppini, M. Delpech, M.B. Pepys, P.N. Hawkins, V. Bellotti. - In: NEW ENGLAND JOURNAL OF MEDICINE. - ISSN 0028-4793. - 366:24(2012 Jun 14), pp. 2276-2283. [10.1056/NEJMoa1201356]
Hereditary systemic amyloidosis due to Asp76Asn variant β2-microglobulin
S. Ricagno;M. Bolognesi;
2012
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.File | Dimensione | Formato | |
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