A new AAT allele (PI Zbristol)
has been discovered in a woman with an obstetric history of three
perinatal deaths from fulminant liver disease and no living offspring.
She and her father were both
PI M1Zbristol heterozygotes. The
Zbristol protein is active as a proteinase inhibitor 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 side of Z and lacks the normal pattern of secondary isoforms
associated with the
commonly occurring AAT variants and migrates faster than normal on an SDS
electrophoresis gel.
The Zbristol mutation was found to 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 glycosylation at residue
83 in the PI Zbristol protein and explains the protein isoelectric
focusing and SDS gel electrophoresis
results. An analysis of haplotypes in the propositus and her father
indicated that the Zbristol mutation
occurred on the common M1(Val 213) genetic background.
The new mutation also led to the
generation of an NlaIII restriction endonuclease recognition site.
Cell lines from two offspring tested
for the presence of this NlaIII site revealed that one had the
variant and the other did not. Thus,
the relationship between Zbristol and fulminant liver disease
in the offspring is unclear.