Hereditary systemic amyloidosis due to Asp76Asn variant β2-microglobulin.
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.
Laboratoire 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
Sophie
S
Valleix
Julian D
JD
Gillmore
Frank
F
Bridoux
Palma P
PP
Mangione
Ahmet
A
Dogan
Brigitte
B
Nedelec
Mathieu
M
Boimard
Guy
G
Touchard
Jean-Michel
JM
Goujon
Corinne
C
Lacombe
Pierre
P
Lozeron
David
D
Adams
Catherine
C
Lacroix
Thierry
T
Maisonobe
Violaine
V
Planté-Bordeneuve
Julie A
JA
Vrana
Jason D
JD
Theis
Sofia
S
Giorgetti
Riccardo
R
Porcari
Stefano
S
Ricagno
Martino
M
Bolognesi
Monica
M
Stoppini
Marc
M
Delpech
Mark B
MB
Pepys
Philip N
PN
Hawkins
Vittorio
V
Bellotti
D028226:Amyloidosis, Familial / Q000150:complications / Q000235:genetics*; D003967:Diarrhea / Q000209:etiology; D005260:Female; D005799:Genes, Dominant; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D020836:Protein Structure, Quaternary; D020543:Proteome / Q000235:genetics; D012859:Sjogren's Syndrome / Q000150:complications / Q000235:genetics; D001613:beta 2-Microglobulin / Q000737:chemistry / Q000235:genetics*
D020543:Proteome; D001613:beta 2-Microglobulin