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

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112 Scopus citations


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 languageEnglish (US)
Pages (from-to)2276-2283
Number of pages8
JournalNew England Journal of Medicine
Issue number24
StatePublished - Jun 14 2012

ASJC Scopus subject areas

  • Medicine(all)


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