Direct Search for Nucleotide Substitutions Responsible for Defects of Alpha 1-Antitrypsin Molecules in Patients with Pulmonary Emphysema.

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The concept that the protease-antiprotease imbalance leads to the chronic destruction of the constituent proteins including elastin in the lower respiratory tracts came from the discovery of cases with alpha1-antitrypsin (alpha1AT) deficiency and early onset of pulmonary emphysema (PE). Most patients with PE, however, have normal levels of alpha1AT, suggesting one possibility that functional imbalance due to the structural changes in the alpha1AT molecule is responsible for destruction. In this study we examined this possibility by direct sequencing along the amino acid coding regions of alpha1AT gene in patients with PE. Although we selected 10 patients (50-60 y. o.) with relatively early onset of PE, we only found same nucleotide substitutions as in the normal alpha1AT variants but no amino scid substitutions responsible for emphysema. In contrast, a 38 y. o. male with alpha1AT deficiency and emphysema was refereed and his alpha1AT gene was analyzed. There was C to T substitution in the second exon causing Ser^<53> (TCC) to Phe^<53> (TTC) mutation. This new variant migrated to S position on isoelectric focusing thus is designated as Siiyama after hia birthplace. Interestingly, using allele specific PCR, 4 other independent families among 9 alpha1AT deficient families reported in Japan were shown to have the same nucleotide substitution, suggesting this variant might be frequent in Japan. In the context of that the Z variant (.. Ala^<213>.. Lys^<342>..). a high frequent deficient variant among Caucasians, is not found in Japan, we analyzed the normal and evolutionary old substitution of Ala^<213>(GCG) to Val^<213>(GTG) using BstPI (G/GANTCC) and found all 156 Japanese analyzed have Val^<213>. This indicates that Japanese (and probably other Oriental peoples) are segregated from Caucasians somehow in the prehistoric era and hardly have the Z variant which keeps old Ala^<213> residue.