Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0034067 (emphysema)
 11,506 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Deficiency of alpha 1-antitrypsin (alpha 1AT), a plasma serine protease inhibitor, increases the risk of precocious pulmonary emphysema. Patients with alpha 1AT deficiency in Japan are extremely rare and no Z type alpha 1AT deficiency, which is one of the most frequent genetic disorders among Caucasians, are reported in Japan at the level of gene analysis. It is not yet clear why Z type alpha 1AT is rare among Japanese. When Ala213(GCG)-Val213(GTG) mutation in the alpha 1AT gene was examined by restriction endonuclease BstPI, all of 156 Japanese samples were Val213(GTG) in contrast to the finding that 30% of U.S. Caucasians are Ala213(GCG), indicating that alpha 1AT genes among Japanese were diverted from M1(Val213) variant and are different from M1(Ala213) variant, from which Z variant was likely diverted. This may explain why Z type alpha 1AT deficiency is not found among Japanese. A new alpha 1AT deficient variant, Siiyama (Ser53(TCC)-Phe53(TTC)), was found in a 39-year-old male with pulmonary emphysema (Seyama K, et al, J Biol Chem, 266, 12627, 1991). Interestingly, 6 out of 10 families with alpha 1AT deficiency in Japan shared the identical substitution as Siiyama. This indicates that although Caucasian type Z alpha 1AT deficiency is not found, Siiyama variant may be relatively common in Japan and even in other oriental countries because of the historical migration of people.
 ...
PMID:[Alpha 1-antitrypsin genes in patients with alpha 1AT deficiency in Japan: mutational analysis and allelic background]. 143 14

alpha 1-antitrypsin (alpha 1AT), a plasma serine protease inhibitor, increases the risk of precocious pulmonary emphysema in individuals when deficient. Although more than 25 years have passed since a deficiency in the serum level of alpha 1AT was reported, it is only recently that the consequence of the amino acid replacement which leads to the deficient state has been discussed in terms of the crystallographic structure of alpha 1AT and the amino acid residues conserved in the superfamily to which it belongs. Our case involved a 38-year-old Japanese male with alpha 1AT deficiency which was analyzed and identified as a new deficient variant. The serum alpha 1AT of the proband migrated to the S position of the reference serum which is more cathodal than M1, the predominant normal variant, when isoelectric focusing (pH 4.2-4.9) is performed by a combination of Western blotting and crossed immunoelectrophoresis. The new deficient variant is designated as Siiyama after his birthplace. Although liver biopsy specimen showed no apparent pathological findings, PAS-positive with diastase-resistant inclusion bodies and immunoreactive aggregates were detected in several hepatocytes. In addition, similar alpha 1AT mRNA transcript levels were observed in peripheral blood leukocytes from the proband and healthy subjects by Northern analysis. All the coding exons (exon Ic, II, III, IV, and V) of the alpha 1AT gene of the proband and his family were amplified by polymerase chain reaction and followed by direct sequencing. A single missense mutation, Ser53 (TCC) to Phe53 (TTC was identified in exon II of the proband's alpha 1AT gene. All his family examined were heterozygous at this base. Ser53 is one of the most conserved residues as predicted by Huber and Carrell (Huber, R., and Carrell, R. W. (1989) Biochemistry 28, 8951-8966) and is thought to contribute to the organization of the internal core element of the alpha 1AT molecule. The mutational matrix number of Ser to Phe substitution is -3, indicating that this change is evolutionally rare. In this regard, a possible explanation for the deficient state in alpha 1AT Siiyama is that the change from an uncharged polar to a nonpolar amino acid imposed on the conserved serpin backbone exerts severe effects on the integrity of the molecule, and hence alters the intracellular processing of alpha 1AT.
 ...
PMID:Siiyama (serine 53 (TCC) to phenylalanine 53 (TTC)). A new alpha 1-antitrypsin-deficient variant with mutation on a predicted conserved residue of the serpin backbone. 190 28

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)
 ...
PMID:Alpha 1-antitrypsin-deficient variant Siiyama (Ser53[TCC] to Phe53[TTC]) is prevalent in Japan. Status of alpha 1-antitrypsin deficiency in Japan. 852 Jul 84