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Alpha 1-antitrypsin deficiency--a defect in secretion.

¹Department of Pharmaceutical Chemistry, School of Pharmacy, London, UK.

Bioscience Reports

|April 1, 1987

Summary

A specific mutation in alpha 1-antitrypsin causes a protein misfolding and secretion defect in liver cells. This defect is not limited to hepatocytes and doesn't require protein glycosylation.

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Area of Science:

Molecular Biology
Genetics
Cell Biology

Background:

Alpha 1-antitrypsin (AAT) deficiency is a genetic disorder.
A common mutation (Z mutation) impairs AAT protein secretion from hepatocytes.

Purpose of the Study:

Investigate the mechanism of impaired AAT secretion due to the Z mutation.
Determine if the secretion defect is specific to hepatocytes and dependent on glycosylation.

Main Methods:

Site-directed mutagenesis to create the Z mutation.
Expression studies in Xenopus oocytes as a model secretory cell.
Analysis of protein translocation, glycosylation, and secretion.

Main Results:

The Z mutation causes a glutamic acid to lysine substitution at residue 342.
Mutant AAT is translocated into the ER and core glycosylated but inefficiently secreted.
Impaired secretion occurs in non-hepatocyte cells (Xenopus oocytes).
Glycosylation is not essential for the observed secretion block.

Conclusions:

The Z mutation induces an intracellular transport defect affecting AAT secretion.
This defect is a general cellular issue, not exclusive to hepatocytes.
Protein glycosylation is not the primary cause of the secretion defect.

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