The molecular basis of alpha 1-antichymotrypsin deficiency in a heterozygote with liver and lung disease.
Alpha 1-antichymotrypsin (alpha 1-ACT) is a serine proteinase inhibitor (serpin) with cathepsin G, mast cell chymase and chymotrypsin as target enzymes. We present the case of a middle-aged man with low plasma levels of alpha 1-ACT, asthma with progression to emphysema, and chronic HCV positive liver disease with selective accumulation of alpha 1-ACT in hepatocytes. This secretory defect is analogous to that seen in Pi Z alpha 1-antitrypsin deficiency. The molecular basis of alpha 1-ACT deficiency in this patient has been characterized by direct sequencing of the alpha 1-ACT genes from the patient and his father. A C-->G transversion in exon III causing a 229Pro-->Ala substitution is proposed to cause a conformational change resulting in abnormal transport through the RER. This mutation was found in one of 20 additional tested patients with chronic obstructive lung disease, but in no control. Two additional polymorphisms of the gene have been identified in unrelated healthy individuals with normal plasma alpha 1-ACT levels. The alpha 1-ACT deficiency state may predispose to obstructive lung disease and influence the course of liver disease. Identification of a specific mutation allows identification of heterozygotes for this deficiency allowing future evaluation of its clinical significance.
Faber
J P
JP
Institut für Klinische Biochemie, Universität Bonn, Germany.
Poller
W
W
Olek
K
K
Baumann
U
U
Carlson
J
J
Lindmark
B
B
Eriksson
S
S
D000595:Amino Acid Sequence; D001483:Base Sequence; D003001:Cloning, Molecular; D004247:DNA / Q000032:analysis / Q000235:genetics; D004646:Emphysema / Q000201:enzymology / Q000209:etiology; D005192:Family Health; D006526:Hepatitis C / Q000201:enzymology / Q000209:etiology; D006579:Heterozygote; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D008099:Liver / Q000201:enzymology / Q000382:microbiology / Q000473:pathology; D008103:Liver Cirrhosis / Q000201:enzymology / Q000209:etiology; D008107:Liver Diseases / Q000201:enzymology* / Q000209:etiology* / Q000382:microbiology; D008171:Lung Diseases / Q000201:enzymology* / Q000209:etiology*; D008173:Lung Diseases, Obstructive / Q000201:enzymology / Q000209:etiology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011487:Protein Conformation; D000514:alpha 1-Antichymotrypsin / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics*
D000514:alpha 1-Antichymotrypsin; D004247:DNA