Structure and expression of the genes coding for human alpha 1-acid glycoprotein

Area of Science:

• Genetics
• Molecular Biology
• Biochemistry

Background:

• Alpha 1-acid glycoprotein (alpha AGP) is a human plasma protein with known structure but unclear function.
• Protein sequencing revealed significant heterogeneity in purified alpha AGP.
• The genetic basis for alpha AGP heterogeneity was previously unknown.

Purpose of the Study:

• To investigate the genetic basis of alpha 1-acid glycoprotein heterogeneity.
• To identify and characterize the alpha AGP coding regions in the human genome.
• To determine the expression patterns and regulation of alpha AGP genes during acute phase response.

Main Methods:

• Cloning of the genomic DNA segment encoding alpha AGP.
• Southern blot analysis to assess the alpha AGP gene cluster.
• mRNA analysis in human liver and Hep3B hepatoma cells.
• In vitro study of acute phase reaction using LPS-stimulated monocytes.

Main Results:

• Identified three adjacent alpha AGP coding regions (AGP-A, B, B') with identical exon-intron structure but varying coding potential.
• Confirmed that the cloned cluster represents all alpha AGP coding sequences in the human genome.
• Demonstrated that AGP-A is the predominant mRNA transcribed in human liver, while AGP-B and B' mRNA levels are low.
• Showed that only AGP-A is strongly induced in Hep3B cells during an in vitro acute phase reaction.

Conclusions:

• The heterogeneity in alpha 1-acid glycoprotein observed at the protein level is explained by the presence of multiple, distinct coding regions (AGP-A, B, B').
• Alpha AGP-A is the major functional gene, responsible for the majority of alpha AGP mRNA in the liver and its induction during acute phase responses.
• This study provides a molecular basis for understanding alpha AGP expression and its role in physiological and pathological conditions.