Hereditary systemic amyloidosis due to Asp76Asn variant β2-microglobulin

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

doi:10.1056/NEJMoa1201356

Hereditary systemic amyloidosis due to Asp76Asn variant β2-microglobulin

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

Laboratory Medicine and Pathology

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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 β₂- microglobulin. Unlike patients with dialysis-related amyloidosis caused by sustained high plasma concentrations of wild-type β₂- microglobulin, the affected members of this kindred had normal renal function and normal circulating β₂-microglobulin values. The Asp76Asn β₂-microglobulin variant was thermodynamically unstable and remarkably fibrillogenic in vitro under physiological conditions. Previous studies of β₂-microglobulin aggregation have not shown such amyloidogenicity for single-residue substitutions. Comprehensive biophysical characterization of the β₂-microglobulin variant, including its 1.40-Å, three-dimensional structure, should allow further elucidation of fibrillogenesis and protein misfolding.

Original language	English (US)
Pages (from-to)	2276-2283
Number of pages	8
Journal	New England Journal of Medicine
Volume	366
Issue number	24
DOIs	https://doi.org/10.1056/NEJMoa1201356
State	Published - Jun 14 2012

ASJC Scopus subject areas

Medicine(all)

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Valleix, S., Gillmore, J. D., Bridoux, F., Mangione, P. P., Dogan, A., Nedelec, B., Boimard, M., Touchard, G., Goujon, J. M., Lacombe, C., Lozeron, P., Adams, D., Lacroix, C., Maisonobe, T., Planté-Bordeneuve, V., Vrana, J. A., Theis, J. D., Giorgetti, S., Porcari, R., ... Bellotti, V. (2012). Hereditary systemic amyloidosis due to Asp76Asn variant β2-microglobulin. New England Journal of Medicine, 366(24), 2276-2283. https://doi.org/10.1056/NEJMoa1201356

Valleix, S, Gillmore, JD, Bridoux, F, Mangione, PP, Dogan, A, Nedelec, B, Boimard, M, Touchard, G, Goujon, JM, Lacombe, C, Lozeron, P, Adams, D, Lacroix, C, Maisonobe, T, Planté-Bordeneuve, V, Vrana, JA, Theis, JD, Giorgetti, S, Porcari, R, Ricagno, S, Bolognesi, M, Stoppini, M, Delpech, M, Pepys, MB, Hawkins, PN & Bellotti, V 2012, 'Hereditary systemic amyloidosis due to Asp76Asn variant β2-microglobulin', New England Journal of Medicine, vol. 366, no. 24, pp. 2276-2283. https://doi.org/10.1056/NEJMoa1201356

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title = "Hereditary systemic amyloidosis due to Asp76Asn variant β2-microglobulin",

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 β2- microglobulin. Unlike patients with dialysis-related amyloidosis caused by sustained high plasma concentrations of wild-type β2- microglobulin, the affected members of this kindred had normal renal function and normal circulating β2-microglobulin values. The Asp76Asn β2-microglobulin variant was thermodynamically unstable and remarkably fibrillogenic in vitro under physiological conditions. Previous studies of β2-microglobulin aggregation have not shown such amyloidogenicity for single-residue substitutions. Comprehensive biophysical characterization of the β2-microglobulin variant, including its 1.40-{\AA}, three-dimensional structure, should allow further elucidation of fibrillogenesis and protein misfolding.",

author = "Sophie Valleix and Gillmore, {Julian D.} and Frank Bridoux and Mangione, {Palma P.} and Ahmet Dogan and Brigitte Nedelec and Mathieu Boimard and Guy Touchard and Goujon, {Jean Michel} and Corinne Lacombe and Pierre Lozeron and David Adams and Catherine Lacroix and Thierry Maisonobe and Violaine Plant{\'e}-Bordeneuve and Vrana, {Julie A.} and Theis, {Jason D.} and Sofia Giorgetti and Riccardo Porcari and Stefano Ricagno and Martino Bolognesi and Monica Stoppini and Marc Delpech and Pepys, {Mark B.} and Hawkins, {Philip N.} and Vittorio Bellotti",

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AU - Valleix, Sophie

AU - Gillmore, Julian D.

AU - Bridoux, Frank

AU - Mangione, Palma P.

AU - Dogan, Ahmet

AU - Nedelec, Brigitte

AU - Boimard, Mathieu

AU - Touchard, Guy

AU - Goujon, Jean Michel

AU - Lacombe, Corinne

AU - Lozeron, Pierre

AU - Adams, David

AU - Lacroix, Catherine

AU - Maisonobe, Thierry

AU - Planté-Bordeneuve, Violaine

AU - Vrana, Julie A.

AU - Theis, Jason D.

AU - Giorgetti, Sofia

AU - Porcari, Riccardo

AU - Ricagno, Stefano

AU - Bolognesi, Martino

AU - Stoppini, Monica

AU - Delpech, Marc

AU - Pepys, Mark B.

AU - Hawkins, Philip N.

AU - Bellotti, Vittorio

PY - 2012/6/14

Y1 - 2012/6/14

N2 - 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 β2- microglobulin. Unlike patients with dialysis-related amyloidosis caused by sustained high plasma concentrations of wild-type β2- microglobulin, the affected members of this kindred had normal renal function and normal circulating β2-microglobulin values. The Asp76Asn β2-microglobulin variant was thermodynamically unstable and remarkably fibrillogenic in vitro under physiological conditions. Previous studies of β2-microglobulin aggregation have not shown such amyloidogenicity for single-residue substitutions. Comprehensive biophysical characterization of the β2-microglobulin variant, including its 1.40-Å, three-dimensional structure, should allow further elucidation of fibrillogenesis and protein misfolding.

AB - 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 β2- microglobulin. Unlike patients with dialysis-related amyloidosis caused by sustained high plasma concentrations of wild-type β2- microglobulin, the affected members of this kindred had normal renal function and normal circulating β2-microglobulin values. The Asp76Asn β2-microglobulin variant was thermodynamically unstable and remarkably fibrillogenic in vitro under physiological conditions. Previous studies of β2-microglobulin aggregation have not shown such amyloidogenicity for single-residue substitutions. Comprehensive biophysical characterization of the β2-microglobulin variant, including its 1.40-Å, three-dimensional structure, should allow further elucidation of fibrillogenesis and protein misfolding.

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Hereditary systemic amyloidosis due to Asp76Asn variant β2-microglobulin

Abstract

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