α1-Antitrypsin (α1AT) deficiency is characterized by reduced serum levels of α1AT and a risk for the development of emphysema and liver disease. However, whereas there is an increased risk for emphysema associated with at least 10 α1AT deficiency and null alleles, the hepatic disease is observed only in a subset of these alleles, suggesting that it is not the reduced serum levels of α1AT per se which cause the liver disease. The present study characterizes the α1AT deficiency allele M(malton), an allele that like the common Z deficiency mutation (Glu342 → Lys) is associated with both α1AT deficiency and hepatic disease. Capitalizing on the identification of the homozygous inheritance of the rare M(malton) α1AT deficiency allele, it was demonstrated that although caused by a very different mutation, the M(malton) allele shares with the Z allele the association of liver disease with the same type of abnormalities of α1AT biosynthesis. Cloning of the M(malton) gene and sequence analysis demonstrated that it differs from the normal α1AT M2 allele by deletion of the entire codon (TTC) for residue Phe52. Liver biopsy of the M(malton) homozygote revealed inflammation, mild fibrosis, and intrahepatocyte accumulation of α1AT. Evaluation of de novo α1AT biosynthesis in α1AT synthesizing cells of this individual demonstrated normal levels of α1AT mRNA transcripts but abnormal intracellular accumulation of newly synthesized α1AT at the level of the rough endoplasmic reticulum with consequent reduced α1AT secretion. Finally, retroviral gene transfer of a normal α1AT cDNA and an α1AT cDNA with the M(malton) Phe52 deletion into murine cells demonstrated that the M(malton) cells reproduced the abnormal accumulation of newly synthesized α1AT, thus directly demonstrating that the deletion mutation is responsible for the intracellular accumulation of the newly synthesized α1AT. Thus, not only is the liver disease associated with α1AT deficiency restricted to a subset of α1AT deficiency alleles, it appears to be restricted to those alleles associated with intracellular accumulation of newly synthesized α1AT, suggesting that it is the abnormal intrahepatocyte α1AT accumulation which incites the liver injury.

Original languageEnglish
Pages (from-to)13938-13945
Number of pages8
JournalJournal of Biological Chemistry
Issue number23
StatePublished - 1989


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