Alpha 1-antitrypsin-deficient variant Siiyama (Ser53[TCC] to Phe53[TTC]) is prevalent in Japan. Status of alpha 1-antitrypsin deficiency in Japan.

Abstract

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)

Rare alpha-1-antitrypsin variants: are they really so rare?

“…These data suggest that rare variants may be more common in areas where the main deficient variants (e.g. PI*Z) are less prevalent [Stolk et al 2006], such as Japan, where the most common variant is deficient PI*Siiyama (Ser53Phe), present in most α1-AT-deficient patients [Seyama et al 1995]. The low prevalence of rare variants recently reported in Ireland (0.7%), where the PI*S and PI*Z major AAT variants showed frequencies of 0.05 and 0.02, respectively [Carroll et al 2011], similar to the highest found in European countries, seems to reinforce this hypothesis of an inverse relationship between the more frequent PI*S/ PI*Z variants and rare AAT variants.…”

Alpha One Antitrypsin Deficiency: From Gene to Treatment

“…In addition, the expression of liver disease varies widely, from jaundice only at birth, through to cirrhosis, perhaps because of other genetic influences on this aspect of the clinical phenotype [26]. Polymerisation of AAT in this way also underlies the PiMmalton (52Phe deleted) [27] and Siiyama (Ser53Phe) [28,29,30] forms of AATD, that are common in Sardinia and Japan, respectively. A slower rate of polymer formation occurs with the PiS allele (Glu264Val), because the structural change in β-sheet A is not as radical [31, 32], resulting in a milder serum deficiency but little evidence of clinical disease.…”

Alpha-1 Antitrypsin Deficiency – A Genetic Risk Factor for COPD

“…The Siiyama allele is the most common cause of AATD in Japan (Seyama et al 1995), while the Mmalton variant (also known as Mcagliari and Mnichinan) is the most commonly found allele in Sardinia ).…”