alpha1-Antitrypsin deficiency, chronic obstructive pulmonary disease and the serpinopathies.
alpha1-Antitrypsin is the prototypical member of the serine proteinase inhibitor or serpin superfamily of proteins. The family includes alpha1-antichymotrypsin, C1 inhibitor, antithrombin and neuroserpin, which are all linked by a common molecular structure and the same suicidal mechanism for inhibiting their target enzymes. Point mutations result in an aberrant conformational transition and the formation of polymers that are retained within the cell of synthesis. The intracellular accumulation of polymers of mutant alpha1-antitrypsin and neuroserpin results in a toxic gain-of-function phenotype associated with cirrhosis and dementia respectively. The lack of important inhibitors results in overactivity of proteolytic cascades and diseases such as COPD (chronic obstructive pulmonary disease) (alpha1-antitrypsin and alpha1-antichymotrypsin), thrombosis (antithrombin) and angio-oedema (C1 inhibitor). We have grouped these conditions that share the same underlying disease mechanism together as the serpinopathies. In the present review, the molecular and pathophysiological basis of alpha1-antitrypsin deficiency and other serpinopathies are considered, and we show how understanding this unusual mechanism of disease has resulted in the development of novel therapeutic strategies.
Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Cambridge CB2 0XY, U.K.
Ugo I
UI
Ekeowa
Bibek
B
Gooptu
Didier
D
Belorgey
Peter
P
Hägglöf
Susanna
S
Karlsson-Li
Elena
E
Miranda
Juan
J
Pérez
Ian
I
MacLeod
Heike
H
Kroger
Stefan J
SJ
Marciniak
Damian C
DC
Crowther
David A
DA
Lomas
D005838:Genotype; D006801:Humans; D010641:Phenotype; D017354:Point Mutation / Q000235:genetics; D029424:Pulmonary Disease, Chronic Obstructive / Q000209:etiology* / Q000628:therapy; D015842:Serine Proteinase Inhibitors / Q000627:therapeutic use*; D015843:Serpins / Q000172:deficiency*; D019896:alpha 1-Antitrypsin Deficiency / Q000235:genetics* / Q000628:therapy
D015842:Serine Proteinase Inhibitors; D015843:Serpins