In contrast to the fact that alpha 1-antitrypsin (alpha 1-AT) deficiency is one of the most common hereditary disorders of Caucasians, deficient variants among Orientals have been recognized to be extremely rare. Only 12 cases of alpha 1-AT deficiency have been reported in Japan, including five cases in which the genetic defects have already been elucidated: Mnichinan (delta Phe52[TTC] and Gly148[GGG]-->Arg148[AGG]), two unrelated cases of Siiyama (Ser53[TCC]-->Phe53[TTC]), a heterozygote of Mmalton (delta Phe52[TTC]), and one additional case of 14q- syndrome (sporadic deletion of the neighboring region of the alpha 1-AT gene locus). alpha 1-AT Siiyama is a deficient variant originally identified in a 38-yr-old patient with pulmonary emphysema in Japan. The amino acid substitution in this variant occurs in a highly conserved residue of the serpin (serine protease inhibitor) backbone (Seyama K, et al. 1991. J. Biol. Chem. 266:12627-12632). We attempted to determine whether alpha 1-AT deficiency in Japan was caused by independent genetic defects or whether it shared some common mutations in the alpha 1-AT gene. We examined five of seven available families for which the genetic defects causing alpha 1-AT deficiency have not yet been explored. When the allele-specific polymerase chain reaction (PCR) was performed with a pair of oligonucleotide primers having the mutated base sequence of the alpha 1-AT Siiyama allele at the 3' end, all eight cases of alpha 1-AT deficiency among five unrelated families turned out to be homozygous carriers of the alpha 1-AT Siiyama mutation.(ABSTRACT TRUNCATED AT 250 WORDS)