Alternative titles; symbols
HGNC Approved Gene Symbol: SERPINA3
Cytogenetic location: 14q32.13 Genomic coordinates (GRCh38) : 14:94,612,391-94,624,053 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 14q32.13 | Alpha-1-antichymotrypsin deficiency | 3 | ||
| Cerebrovascular disease, occlusive | 3 |
Alpha-1-antichymotrypsin is a plasma protease inhibitor synthesized in the liver. It is a single glycopeptide chain of about 68,000 daltons and belongs to the class of serine protease inhibitors. In man, the normal serum level is about one-tenth that of alpha-1-antitrypsin (PI; 107400), with which it shares nucleic acid and protein sequence homology (Chandra et al., 1983). Both are major acute phase reactants; their concentrations in plasma increase in response to trauma, surgery, and infection. Antithrombin III, which also is structurally similar to alpha-1-antitrypsin, shows less sequence homology to antichymotrypsin and is not an acute phase reactant.
Kelsey et al. (1988) cloned and analyzed the AACT gene, partly because of the possibility that genetic variation in other protease inhibitors may influence the prognosis in AAT deficiency. They isolated the AACT gene on a series of cosmid clones, with restriction mapping of about 70 kb around the gene.
By yeast 2-hybrid analysis, Kroczynska et al. (2004) found that DNAJC1 (611207) interacted with AACT, and they confirmed the interaction by dot blot, native electrophoresis, and fluorescence studies. The second SANT domain of DNAJC1 (SANT2) was sufficient to bind AACT both in yeast and in vitro, and the interaction was disrupted by a trp520-to-ala mutation in SANT2. AACT bound to SANT2 had no inhibitory activity toward chymotrypsin (see 118890). SANT2 significantly slowed formation of the AACT-chymotrypsin acyl complex with no significant effect on the catalytic efficiency of chymotrypsin.
Eriksson et al. (1986) studied levels of antichymotrypsin in 229 patients with liver disease verified by biopsy. In a small subgroup with seronegative, chronic, active hepatitis, they found low ACT values. In 1 of these patients they found equally low AACT levels among first-degree relatives, prompting a study of other cases of partial deficiency, i.e., those with approximately 50% of normal plasma levels. Six of 8 AACT-deficient individuals, over 25 years of age, had liver manifestations and 3 of 8 had pulmonary defects, varying from severe disease to subtle laboratory abnormalities. The abnormal gene was inherited in an autosomal dominant manner, and its frequency was estimated to be 0.003.
Rabin et al. (1985) found by in situ hybridization that the AACT gene maps to 14q31-q32.3, which overlaps the region to which PI has been mapped (14q24.3-q32.1) by study of somatic cell hybrids. PI and AACT may constitute a gene cluster: in situ hybridization shows that both map to the 14q31-q32.3 region (Rabin et al., 1986). Indeed, Sefton et al. (1989) demonstrated that the PI and the AACT genes are located on the same 360-kb MluI restriction fragment by pulsed field gel electrophoresis. Sefton et al. (1990) concluded that the PI-PIL gene cluster is only 220 kb away from the AACT gene and that it is oriented in the opposite direction. (PIL refers to 'PI-like' and is also referred to as 'antitrypsin-related,' or ATR (107410).) The comparatively short interval between the genes came as a surprise given previous estimates of the level of genetic recombination between them.
Kelsey et al. (1988) found that a common TaqI polymorphism was tightly linked to the PI gene (maximum lod score in males = 2.29 at theta = 0; in females 6.11 at theta = 0.032). PI-AACT haplotypes in 31 families ascertained through subjects with the PI*Z allele did not show any linkage disequilibrium, and the distribution of RFLP alleles in 16 unrelated PI*Z patients presenting with childhood liver disease and 5 unrelated PI*Z patients with adult chest disease did not differ significantly from each other.
Kamboh et al. (1995) presented evidence that a polymorphism of AACT (107280.0005) in combination with the APOE4 allele (107741.0016) increases susceptibility to Alzheimer disease (104300). The polymorphism results in the presence of either an alanine (the A allele, symbolized ACT*A by them) or threonine (the T allele, symbolized ACT*T by them) at residue -15 of the AACT signal peptide. Haines et al. (1996, 1997) cast doubt on the findings by Kamboh et al. (1995, 1997) on the association of this allele with Alzheimer disease.
Yamamoto et al. (1997) found a significant association between homozygosity for the ACT*A allele and susceptibility to Parkinson disease (168600), with a relative risk ratio of 3.36 compared to ACT*T homozygotes in a Japanese population. This effect was independent of APOE status. In contrast, Munoz et al. (1999) found no association between this ACT polymorphism and Parkinson disease in a Spanish population.
Morgan et al. (1997) found that a dinucleotide microsatellite allele in the 5-prime-flanking sequence of the ACT gene, designated A10, in association with APOE*4 significantly increased the risk of developing sporadic Alzheimer disease (104300).
Wang et al. (2002) presented data indicating that the ACT gene harbors several potentially important variable sites, which are associated with either increased or decreased risk of Alzheimer disease. The nonrandom combination of risk and protective alleles may explain, in part, why the association studies regarding the ACT codon -17*A polymorphism have been inconsistent, especially if the frequency of other ACT mutations vary between populations.
Morgan et al. (2001) described a G-to-T polymorphism in the promoter region of the ACT gene with the T allele being associated with a 22% increase in the mean plasma ACT concentrations. By reporter gene studies, the T allele was consistently associated with higher mean basal expression in both a human liver cell line and a human glial cell line. The T allele in the promoter region was in almost complete linkage disequilibrium with the T allele in the signal peptide region of the ACT gene. The authors stated that this was the first description of a polymorphism in the ACT gene promoter directly associated with altered gene expression.
While cigarette smoking is a major cause of COPD, only 15% of smokers develop the disease, indicating major genetic influences. The most widely recognized candidate gene in COPD is SERPINA1 (107400), although it has been suggested that SERPINA3 may also play a role. Chappell et al. (2006) identified 15 single-nucleotide polymorphism (SNP) haplotype tags from high-density SNP maps of the 2 genes and evaluated these SNPs in the largest case-control genetic study of COPD conducted to that time. For SERPINA1, 6 newly identified haplotypes with a common backbone of 5 SNPs were found to increase the risk of disease by 6- to 50-fold, the highest risk of COPD that had been reported. In contrast, no haplotype associations for SERPINA3 were identified.
By PCR-single strand conformation polymorphism (SSCP) analysis, Tsuda et al. (1992) identified a point mutation in exon 5 of the AACT gene resulting in substitution of met by val at codon 389. The mutation, an A-to-G transition at basepair 1252, was found in heterozygous state in 6 patients; 4 of the 6 (aged 38, 43, 69, and 80 years) had occlusive cerebrovascular disease.
In 35 individuals with non-AD dementia (primarily vascular) and 100 with Alzheimer-type dementia, Gilfix and Briones (1997) found none that carried the met389-to-val polymorphism. The polymorphism was also not found in 59 North American controls.
Tachikawa et al. (2001) found that the frequency of the met389-to-val variant of AACT was higher in a group with ischemic cerebrovascular disease than in a control group, which appeared to be independent of known risk factors. They subdivided the cerebrovascular disease group into lacunar and atherothrombotic subgroups. Atherothrombotic infarction occurs with atherosclerosis involving selected sites in extracranial and major intracranial arteries. The term lacunar-type infarction is used to refer to small lesions that result from the involvement of deep, small, penetrating arteries. Further analysis by subtype showed association of the mutation particularly with lacunar infarction.
Tsuda et al. (1992) used PCR-SCCP and direct sequencing to demonstrate a variant AACT: deletion of 2 bases (AA) from codon 391 (AAA for lys) led to a frameshift, a change in the amino acid sequence downstream of the deletion, and elongation of the peptide chain by 10 amino acids. The subject was a 26-year-old asymptomatic male. The concentration of serum AACT was about 40% of the normal level, suggesting that the variant molecule is not secreted from the liver or is rapidly degraded.
Using denaturing gradient gel electrophoresis and direct sequencing of amplified genomic DNA, Poller et al. (1993) identified 2 defective mutants of the human AACT gene associated with chronic obstructive pulmonary disease (COPD). A CTG (leu) to CCG (pro) transition in codon 55 was found in affected members in 3 successive generations.
In 4 patients with COPD and a positive family history for COPD, Poller et al. (1993) observed a CCT (pro)-to-GCT (ala) transversion in codon 229. (Poller et al. (1992) referred to this mutation as PRO227ALA.) Samilchuk and Chuchalin (1993) failed to find this mutation among 102 COPD patients treated in Moscow hospitals.
The polymorphism discussed by Kamboh et al. (1995) results in the presence of either an alanine (the A allele, symbolized ACT*A by them) or threonine (the T allele, symbolized ACT*T by them) at residue -15 of the AACT signal peptide; their 'AA' genotype is biallelic for ACT*A, while genotypes 'AT' and 'TT' have 1 and no ACT*A alleles, respectively. The frequency of the 2 alleles ACT*A and ACT*T was approximately equal in the control population and 0.57 and 0.43, respectively, in a group of Alzheimer disease patients. The combination of AA homozygosity with homozygosity of APOE4 (107741.0016) had a frequency of 1/17 in the AD group compared to 1/313 in the general population control. Possible mechanisms for the apparent dependent effect of APOE4 on the AACT signal peptide polymorphism were proposed by Kamboh et al. (1995): the ACT*A allele in the signal peptide may be in strong linkage disequilibrium with a functional mutation affecting an amino acid substitution in the mature AACT protein which possibly enhances the binding of the AACT protein to amyloid beta protein or interacts with APOE to alter binding to microtubular elements. Alternatively, amino acid changes in a signal peptide could affect hydrophobicity and alter the posttranslational protein structure.
Haines et al. (1996) were, however, unable to confirm any effect of the AA/TT polymorphism, either alone or in combination with the APOE4 allele, in a large set of Alzheimer disease families and sporadic Alzheimer cases. Kamboh et al. (1997) felt that the data of Haines et al. (1996) were at least not inconsistent with their own as reported in Kamboh et al. (1995). Haines et al. (1997) retorted and pointed out that 3 additional reports had failed to confirm the findings of Kamboh et al. (1995). Haines et al. (1997) concluded that, in toto, the results suggest that any effect of the ACT signal peptide polymorphism on AD, if it exists at all, is very small.
Chandra, T., Stackhouse, R., Kidd, V. J., Robson, K. J. H., Woo, S. L. C. Sequence homology between human alpha-1-antichymotrypsin, alpha-1-antitrypsin, and antithrombin III. Biochemistry 22: 5055-5061, 1983. [PubMed: 6606438] [Full Text: https://doi.org/10.1021/bi00291a001]
Chappell, S., Daly, L., Morgan, K., Baranes, T. G., Roca, J., Rabinovich, R., Millar, A., Donnelly, S. C., Keatings, V., MacNee, W., Stolk, J., Hiemstra, P., Miniati, M., Monti, S., O'Connor, C. M., Kalsheker, N. Cryptic haplotypes of SERPINA1 confer susceptibility to chronic obstructive pulmonary disease. Hum. Mutat. 27: 103-109, 2006. [PubMed: 16278826] [Full Text: https://doi.org/10.1002/humu.20275]
Eriksson, S., Lindmark, B., Lilia, H. Familial alpha-1-antichymotrypsin deficiency. Acta Med. Scand. 220: 447-453, 1986. [PubMed: 3492865]
Gilfix, B. M., Briones, L. Absence of the A1252G mutation in alpha 1-antichymotrypsin in a North American population suffering from dementia. J. Cereb. Blood Flow Metab. 17: 233-235, 1997. [PubMed: 9040504] [Full Text: https://doi.org/10.1097/00004647-199702000-00014]
Haines, J. L., Pritchard, M. L., Saunders, A. M., Schildkraut, J. M., Growdon, J. H., Gaskell, P. C., Farrer, L. A., Auerbach, S. A., Gusella, J. F., Locke, P. A., Rosi, B. L., Yamaoka, L., Small, G. W., Conneally, P. M., Roses, A. D., Pericak-Vance, M. A. No genetic effect of alpha-1-antichymotrypsin in Alzheimer disease. Genomics 33: 53-56, 1996. [PubMed: 8617509] [Full Text: https://doi.org/10.1006/geno.1996.0158]
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Kroczynska, B., Evangelista, C. M., Samant, S. S., Elguindi, E. C., Blond, S. Y. The SANT2 domain of the murine tumor cell DnaJ-like protein 1 human homologue interacts with alpha-1-antichymotrypsin and kinetically interferes with its serpin inhibitory activity. J. Biol. Chem. 279: 11432-11443, 2004. [PubMed: 14668352] [Full Text: https://doi.org/10.1074/jbc.M310903200]
Morgan, K., Licastro, F., Tilley, L., Ritchie, A., Morgan, L., Pedrini, S., Kalsheker, N. Polymorphism in the alpha-1-antichymotrypsin (ACT) gene promoter: effect on expression in transfected glial and liver cell lines and plasma ACT concentrations. Hum. Genet. 109: 303-310, 2001. [PubMed: 11702211] [Full Text: https://doi.org/10.1007/s004390100575]
Morgan, K., Morgan, L., Carpenter, K., Lowe, J., Lam, L., Cave, S., Xuereb, J., Wischik, C., Harrington, C., Kalsheker, N. A. Microsatellite polymorphism of the alpha-1-antichymotrypsin gene locus associated with sporadic Alzheimer's disease. Hum. Genet. 99: 27-31, 1997. [PubMed: 9003488] [Full Text: https://doi.org/10.1007/s004390050304]
Munoz, E., Obach, V., Oliva, R., Marti, M. J., Ezquerra, M., Pastor, P., Ballesta, F., Tolosa, E. Alpha-1-antichymotrypsin gene polymorphism and susceptibility to Parkinson's disease. Neurology 52: 297-301, 1999. [PubMed: 9932947] [Full Text: https://doi.org/10.1212/wnl.52.2.297]
Poller, W., Faber, J.-P., Scholz, S., Weidinger, S., Bartholome, K., Olek, K., Eriksson, S. Mis-sense mutation of alpha-1-antichymotrypsin gene associated with chronic lung disease. (Letter) Lancet 339: 1538, 1992. [PubMed: 1351206] [Full Text: https://doi.org/10.1016/0140-6736(92)91301-n]
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Rabin, M., Watson, M., Breg, W. R., Kidd, V., Woo, S. L. C., Ruddle, F. H. Human alpha-1-antichymotrypsin and alpha-1-antitrypsin (PI) genes map to the same region on chromosome 14. (Abstract) Cytogenet. Cell Genet. 40: 728, 1985.
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Tachikawa, H., Tsuda, M., Onoe, K., Ueno, M., Takagi, S., Shinohara, Y. Alpha-1-antichymotrypsin gene A1252G variant (ACT Isehara-1) is associated with a lacunar type of ischemic cerebrovascular disease. J. Hum. Genet. 46: 45-47, 2001. [PubMed: 11289720] [Full Text: https://doi.org/10.1007/s100380170125]
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Tsuda, M., Sei, Y., Yamamura, M., Yamamoto, M., Shinohara, Y. Detection of a new mutant alpha-1-antichymotrypsin in patients with occlusive-cerebrovascular disease. FEBS Lett. 304: 66-68, 1992. [PubMed: 1618300] [Full Text: https://doi.org/10.1016/0014-5793(92)80590-d]
Wang, X., DeKosky, S. T., Luedecking-Zimmer, E., Ganguli, M., Kamboh, M. I. Genetic variation in alpha-1-antichymotrypsin and its association with Alzheimer's disease. Hum. Genet. 110: 356-365, 2002. [PubMed: 11941486] [Full Text: https://doi.org/10.1007/s00439-002-0697-3]
Yamamoto, M., Kondo, I., Ogawa, N., Asanuma, M., Yamashita, Y., Mizuno, Y. Genetic association between susceptibility to Parkinson's disease and alpha-1-antichymotrypsin polymorphism. Brain Res. 759: 153-155, 1997. [PubMed: 9219874] [Full Text: https://doi.org/10.1016/s0006-8993(97)00330-2]