Ju. Lovegrove et al., A NEW ALPHA-1-ANTITRYPSIN MUTATION, THR-MET-85, (PI Z(BRISTOL)) ASSOCIATED WITH NOVEL ELECTROPHORETIC PROPERTIES, Annals of Human Genetics, 61, 1997, pp. 385-391
A new AAT allele (PI Z(bristol)) has been discovered in a woman with a
n obstetric history of three perinatal deaths from fulminant liver dis
ease and no living offspring. She and her father were both PI M1Z(bris
tol) heterozygotes. The Z(bristol) protein is active as a proteinase i
nhibitor but appeared to be deficient in the plasma to about the same
degree as the S protein in MS heterozygotes. It focuses on the basic s
ide of Z and lacks the normal pattern of secondary isoforms associated
with the commonly occurring AAT variants and migrates faster than nor
mal on an SDS electrophoresis gel. The Z(bristol) mutation was found t
o be a C to T transition at codon 85 changing ACG (Thr) to ATG (Met).
This disrupts the N-glycosylation site starting at Asn 83 preventing g
lycosylation at residue 83 in the PI Z(bristol) protein and explains t
he protein isoelectric focusing and SDS gel electrophoresis results. A
n analysis of haplotypes in the propositus and her father indicated th
at the Z(bristol) mutation occurred on the common M1(Val 213) genetic
background. The new mutation also led to the generation of an NlaIII r
estriction endonuclease recognition site. Cell lines from two offsprin
g tested for the presence of this NlaIII site revealed that one had th
e variant and the other did not. Thus, the relationship between Z(bris
tol) and fulminant liver disease in the offspring is unclear.