Heat Lability of Alpha₁-Antitrypsin Variants

¹ Department of Respiratory Diseases, City of Hope, Medical Center, Duarte; University of California, Irvine, Calif.

Most genetic mutants of ₁-antitrypsin (AAT), usually associated with deficient serum levels, were found to have increased lability at 55°C. Normal (Pi^MM) AAT in whole serum had a half-life of approximately 60 minutes at 55°C as measured by its serum-trypsin-inhibitory-capacity (STIC), compared to a half-life of 30 minutes for SS, IS and FS phenotypes. Heterozygous combinations of either a "Z," "S," "I" or "P" variant with the normal "M" variant resulted in biphasic heatlability curves at 55°C, and in loss of the specific protein bands for the more labile variant on acid-starch electrophoresis. The V variant and normal heatlability consistent with its normal serum levels. A block in the release of AAT from the liver is most likely the major cause of AAT deficiency with the "Z" variant, but increased lability could contribute to its deficiency in serum. Other Pi variants are not blocked in the liver, and increased lability of these variants in vivo may be the cause of their less severe deficiency states.