α1-Antitrypsin deficiency caused by the α1-antitrypsin Null(mattawa) gene. An insertion mutation rendering the α1-antitrypsin gene incapable of producing α1-antitrypsin

α1-Antitrypsin (α1AT) deficiency is a hereditary disorder associated with reduced serum α1AT levels and the development of pulmonary emphysema. An α1AT gene is defined as 'Null' when no α1AT in serum is attributed to that α1AT gene. Although all α1AT Null genes have identical phenotypic consequences (i.e. no detectable α1AT in the serum), different genotypic mechanisms can cause the Null state. This study defines the molecular basis for the αAT gene Null(mattawa), identified and cloned from genomic DNA of an individual with the Null-Null phenotype and emphysema resulting from the heterozygous inheritance of the Null(mattawa) and Null(bellingham) genes. Sequencing of exons Ic-V and all exon-intron junctions of the Null(mattawa) gene demonstrated it was identical to the common normal M1(Val²¹³) α1AT gene except for the insertion of a single nucleotide within the coding region of exon V, causing a 3' frameshift with generation of a premature stop signal. Family analysis using oligonucleotide probes specific for the Null(mattawa) sequence demonstrated the gene was inherited in an autosomal fashion. Examination of blood monocytes demonstrated that a normal-sized, 1.8-kb α1AT mRNA transcript is associated with the Null(mattawa) gene and in vitro translation of mRNA with the Null(mattawa) mutation showed it translated at a normal rate but produced a truncated α1AT protein. Additionally, retroviral transfer of the α1AT Null(mattawa) cDNA to murine fibroblasts demonstrated no detectable intracellular or secreted α1AT, despite the presence of α1AT Null(mattawa) mRNA transcripts. These findings are consistent with the concept that the molecular pathophysiology of Null(mattawa) is likely manifested at a posttranslational level. The identification of the Null(mattawa) gene supports the concept that Null α1AT alleles represent a heterogenous group in which very different mechanisms cause the identical phenotypic state.