Alternative titles; symbols
HGNC Approved Gene Symbol: SERPINA1
Cytogenetic location: 14q32.13 Genomic coordinates (GRCh38) : 14:94,376,747-94,390,635 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 14q32.13 | Emphysema due to AAT deficiency | 613490 | Autosomal recessive | 3 |
| Emphysema-cirrhosis, due to AAT deficiency | 613490 | Autosomal recessive | 3 | |
| Hemorrhagic diathesis due to antithrombin Pittsburgh | 613490 | Autosomal recessive | 3 |
The SERPINA1 gene encodes alpha-1-antitrypsin (AAT), also known as protease inhibitor (PI), a major plasma serine protease inhibitor. AAT complexes predominantly with elastase, but also with trypsin, chymotrypsin, thrombin, and bacterial proteases. The most important inhibitory action of AAT is that against neutrophil elastase (ELANE, or HLE; 130130), a protease that degrades elastin of the alveolar walls as well as other structural proteins of a variety of tissues (review by Cox, 2001).
Kurachi et al. (1981) cloned a nearly full-length baboon AAT cDNA (approximately 1,352 bp) and a partial human AAT cDNA (approximately 306 bp). They found more than 96% homology between the cDNA and predicted amino acid sequences of AAT in the 2 species. Comparison of baboon AAT, human antithrombin III (107300), and chicken ovalbumin indicated about 30% homology of amino acid sequence.
Long et al. (1984) cloned a full-length human AAT cDNA from a liver cDNA library. Sequence analysis revealed a precursor molecule containing a 24-amino acid signal peptide and a mature protein of 394 amino acids. AAT is primarily synthesized in the liver.
Crystal (1990) noted that hepatocytes are the major source of AAT, but that the gene is also expressed in mononuclear phagocytes and neutrophils.
Lai et al. (1983) showed that the AAT gene contains 3 introns in the peptide-coding region.
Long et al. (1984) found that the genomic length of the PI gene is 10.2 kb with a 1,434-bp coding region. The gene has 4 introns; exon 1, the 5-prime portion of exon 2, and the 3-prime portion of exon 5 are noncoding regions. The first intron, 5.3 kb long, contains a 143-amino acid open reading frame (which does not appear to be an actual protein coding region), an Alu family sequence, and a pseudotranscription initiation region.
Perlino et al. (1987) found that the AAT gene in macrophages is transcribed from a macrophage-specific promoter located about 2,000 bp upstream of the hepatocyte-specific promoter. Transcription from the 2 AAT promoters is mutually exclusive; the macrophage promoter is silent in hepatocytes and the hepatocyte promoter is silent in macrophages. In macrophages, 2 distinct mRNAs are generated by alternative splicing.
Hafeez et al. (1992) demonstrated that the AAT gene has 3 macrophage-specific transcriptional initiation sites upstream from a single hepatocyte-specific transcriptional initiation site. Macrophages use these sites during basal and modulated expression. Hepatoma cells use the hepatocyte-specific transcriptional initiation site during basal and modulated expression but also switch on transcription from the upstream macrophage transcriptional initiation sites during modulation by the acute phase mediator interleukin-6 (IL6; 147620).
Soutoglou and Talianidis (2002) analyzed the ordered recruitment of factors to the human alpha-1-antitrypsin promoter around the initial activation of the gene during enterocyte differentiation. They found that a complete preinitiation complex, including phosphorylated RNA Pol II (180660), was assembled at the promoter long before transcriptional activation. The histone acetyltransferases CBP (600140) and P/CAF (602303) were recruited subsequently, but local histone hyperacetylation was delayed. After transient recruitment of the human Brahma homolog BRM (600014), remodeling of the neighboring nucleosome coincided with transcription initiation. Soutoglou and Talianidis (2002) concluded that, at this promoter, chromatin reconfiguration is a defining step of the initiation process, acting after the assembly of the Pol II machinery.
Lai et al. (1983) used a cloned AAT gene as a hybridization probe to analyze EcoRI-digested genomic DNA from different individuals and identified 2 distinct bands (9.6 kb and 8.5 kb long) in every case. Analysis using only intronic DNA as probe showed that the authentic gene resides in the 9.6-kb fragment. The 8.5-kb fragment was thought to contain a gene with close sequence homology to that of AAT.
By studying hybrids of mouse or rat hepatoma cells with human lymphocytes, Darlington et al. (1982) and Pearson et al. (1981) achieved direct assignment of the PI locus to chromosome 14. From study of 2 families with abnormalities of the long arm of chromosome 14, Cox et al. (1982) localized GM to 14q32.3 and PI to a more proximal position between 14q24.3 and 14q32.1. The immunoglobulin genes are in a chromosome region noted for its high frequency of breaks associated with chromosome rearrangement, occurring both spontaneously in cultured lymphocytes and in certain malignancies.
By in situ hybridization, Schroeder et al. (1985) narrowed the assignment of the PI locus to 14q31-q32. Turleau et al. (1984) studied a patient with an interstitial deletion of 14q and assigned the PI locus to 14q32.1 by exclusion mapping. In a similar patient with an interstitial deletion of 14q, Yamamoto et al. (1986) confirmed the assignment to 14q32.1. By the dosage principle, the level of alpha-1-antitrypsin in the patient was only about half of that in his parents and in controls.
Sefton et al. (1989) used pulsed field gel electrophoresis to demonstrate that the genes encoding alpha-1-antitrypsin and alpha-1-antichymotrypsin (AACT, SERPINA3; 107280) are approximately 220 kb apart and oriented in opposite directions.
Molecular studies of a ring chromosome 14 showed that the IGH and D14S1 loci were missing, whereas the PI locus was present (Keyeux et al., 1989). Thus, PI is proximal to the other 2 loci, a conclusion that was supported by much earlier data. A noncoding alpha-1-antitrypsin-like gene (PIL; 107410) is located 12 kb 3-prime of the AAT gene. Billingsley et al. (1989) found that this gene and the AAT and AACT genes are carried by a single 550-kb NarI fragment. Also see Billingsley et al. (1993).
By in situ hybridization, Ledbetter et al. (1987) localized the AAT locus to mouse chromosome 12.
Dycaico et al. (1988) established transgenic mouse lineages that carried the normal (M) (see 107400.0001) or mutant (Z) (107400.0011) alleles of the human AAT gene. All expressed the human protein in liver, cartilage, gut, kidneys, lymphoid macrophages, and thymus. The human M-allele protein was secreted normally into the serum. However, the human Z-allele protein accumulated in several cell types, particularly in hepatocytes, and was found in serum in concentrations 10 times lower than the M-allele protein. Mice in one lineage carrying the Z allele displayed significant runting in the neonatal period and had developed abnormalities in the liver with accumulation of human Z protein in diastase-resistant cytoplasmic globules that stained with periodic acid-Schiff reaction (PAS).
The major physiologic substrate of alpha-1-antitrypsin is elastase, particularly in the lower respiratory tract (Cox, 2001).
AAT is an acute-phase reactant in that serum levels are increased with inflammation, trauma, and pregnancy (Cox, 1989).
Alpha-1-Antitrypsin Deficiency
Deficiency of alpha-1-antitrypsin (613490) is primarily associated with the risk of emphysema and liver disease; see MOLECULAR GENETICS.
Role in Twinning
Lieberman et al. (1979) found an increased frequency of heterozygosity for antitrypsin deficiency in twins and parents of twins. They concluded that 'increased' fertility and twinning may be heterozygous advantages for antitrypsin deficiency. Clark and Martin (1982) found that the frequency of the S allele (107400.0013) in mothers of dizygotic twins (0.088) was double that in controls (0.044). The frequency of S in the parents of monozygotic twins and in fathers of DZ twins was no higher than in controls. Normal frequencies were observed for the Z allele (107400.0011). No fertility indices other than twinning itself were available. To study relationships between Pi types, fertility, and twinning, Boomsma et al. (1992) studied 90 DZ and 70 MZ Dutch twin pairs and their parents. They found that mothers of dizygotic twins had frequencies of the S and Z alleles that were 3 times higher than those in a control sample. Mothers of identical twins also had a higher frequency of S than controls. The S allele may thus both increase ovulation rate and enhance the success of multiple pregnancies.
Role in Human Immunodeficiency Virus-1 Infection
Bristow (2001) found that decreased human immunodeficiency virus (HIV) infectivity correlated significantly with decreased cell surface expression of leukocyte (neutrophil) elastase (HLE) on monocytes but not lymphocytes. Decreased levels of PI correlated with increased cell surface HLE expression and increased HIV infectivity.
Bristow et al. (2001) showed that decreased HIV viral load correlated with decreased circulating PI. Furthermore, asymptomatic patients manifested deficient levels of active PI. Bristow et al. (2001) noted that deficient levels of PI lead to degenerative lung diseases and suggested that preventing PI deficiency may prevent HIV-associated pathophysiology.
Using subclones of monocytic cell lines, Bristow et al. (2003) showed that HLE localized to the cell surface, but not granules, of HIV-1-permissive clones, and to the granules, but not the cell surface, of HIV-1-nonpermissive clones. Stimulation of nonpermissive clones with lipopolysaccharide and LBP (151990), followed by exogenous PI, induced cell surface HLE expression, resulting in susceptibility to HIV infection. PI appeared to promote HIV coreceptor colocalization with surface HLE, thus permitting HIV infectivity.
Shapiro et al. (2001) showed that, at physiologic concentrations, AAT and CE-2072, a synthetic inhibitor of neutrophil elastase and proteinase-3 (PRTN3; 177020), inhibited HIV-1 production in chronically infected monocytic cell lines, in fresh blood mononuclear cells infected after an activation step, and in permissive HeLa cells. EMSA analysis indicated that AAT suppressed activation of the HIV-1-inducing transcription factor NFKB (see 164011). In 5 individuals with the Z-type AAT mutation (glu342lys; 107400.0011), HIV-1 p24 antigen increased more than 6-fold in whole blood after infection with a monocyte-tropic HIV strain. In contrast, there was no significant increase in blood obtained from healthy volunteers.
By screening a peptide library generated from hemofiltrate, Munch et al. (2007) identified a 20-amino acid peptide from the C-proximal region of alpha-1-antitrypsin, designated virus-inhibitory peptide (VIRIP), as the most potent inhibitor of multiple HIV-1 strains, including those resistant to antiviral drugs. Changes in some VIRIP residues increased its antiviral potency 100-fold. VIRIP blocked HIV-1 entry by interacting with the virus gp41 fusion peptide. Munch et al. (2007) proposed that VIRIP may affect disease progression in HIV-1-infected individuals.
NET Inhibitory Peptides
Neonatal neutrophils fail to form neutrophil extracellular traps (NETs) due to circulating NET inhibitory peptides (NIPs), which are cleavage fragments of A1AT. Using immunofluorescence assays, Campbell et al. (2021) showed that human placenta from both term and preterm pregnancies secreted serine protease A1 (HTRA1; 602194) into fetal circulation. Plasma HTRA1 levels were reduced after delivery, and decreased HTRA1 plasma levels were associated with decreased levels of NIPs. Placental HTRA1 cleaved A1AT after amino acid 382 to generate a C-terminal cleavage fragment of A1AT, termed A1ATM383S-CF, that could inhibit NET formation in vitro. Through NET inhibition, A1ATM383S-CF decreased bacterial killing, but it maintained other key neutrophil activities in vitro. In vivo analysis with wildtype mice showed that mouse placenta also secreted Htra1, and placental Htra1 cleaved A1at to generate A1atM383S-CF and inhibit NET formation by neonatal neutrophils. Analysis with Htra1 -/- and wildtype mice revealed that inhibition of NET formation during experimental neonatal sepsis improved survival.
Fagerhol (1968) suggested that the system of inherited AAT variants be called Pi for protease inhibitor. Cox (1978) reported the recommendations of a workshop on PI nomenclature.
Many electrophoretic variants of serum alpha-1-antitrypsin have been described, beginning with those reported by Axelsson and Laurell (1965). Kueppers and Bearn (1967) studied an Italian family with multiple members heterozygous for an electrophoretic variant that could not be distinguished from that which Axelsson and Laurell (1965) found in a Swedish family.
About 30 variants of alpha-1-antitrypsin had been described by 1981 (Hug et al., 1981). The alleles were given symbols according to the relative electrophoretic mobility of the allele product.
Cox et al. (1987) studied RFLPs associated with the AAT gene. They gave information on extensive variability expressed by the polymorphic information content (PIC) as proposed by Botstein et al. (1980). PI types and M subtypes tended to be associated with specific RFLP haplotypes.
Nukiwa et al. (1988) indicated that approximately 75 AAT alleles had been identified at the protein and/or gene level.
Roychoudhury and Nei (1988) tabulated worldwide gene frequencies for allelic variants M (M1, M2, M3, M4), S, Z, F, I, and V. Cox (1989) and Crystal (1989) reviewed the variants, 'normal' and pathologic, of the PI gene.
'Normal' Alleles
Crystal (1989) listed 10 normal AAT alleles that had been sequenced (107400.0001-107400.0010).
Nukiwa et al. (1988) stated that the most common alleles are the 2 forms of M1, that with valine at position 213 (M1V; 107400.0002) and that with alanine at position 213 (M1A; 107400.0001).
'Risk' Alleles
Crystal (1989) divided AAT 'at risk' alleles into 'deficiency' alleles and 'null' alleles. He stated that except for the rare Pittsburgh allele (107400.0026), which is associated with a bleeding disorder, only those phenotypes comprising 2 'at risk' alleles place the individual at risk for development of disease. Alleles in the 'at risk' class are found almost exclusively among Caucasians of European descent, with the highest frequency in northern Europe. Blacks and Asians are rarely affected.
The most common AAT deficiency allele is the Z allele (glu342-to lys; 107400.0011), which occurs on an M1A (ala213; 107400.0001) haplotype background (Nukiwa et al., 1986). The homozygous ZZ phenotype is associated with a high risk of both emphysema and liver disease. The Z allele reaches polymorphic frequencies in Caucasians and is rare or absent in Asians and blacks (DeCroo et al., 1991; Hutchison, 1998).
Clark et al. (1982) reported the cases of 2 brothers with Weber-Christian panniculitis and the AAT Z phenotype. A younger brother had the Z phenotype without Weber-Christian disease. Along with several earlier reported cases, these observations establish a relationship.
Another common AAT deficiency allele is the S allele (glu264-to-val; 107400.0013), which occurs on an M1V (val213; 107400.0002) haplotype background. Pi*S homozygotes are at no risk of emphysema, but compound heterozygotes with a Z or a null allele have a mildly increased risk (Curiel et al., 1989). The S allele reaches polymorphic frequencies in Caucasians and is rare or absent in Asians and blacks. It is not associated with liver disease.
Other rare deficiency AAT alleles may result in increased risk for both liver and lung disease (e.g., Pi M(Malton); 107400.0012) or only emphysema (e.g., Pi M(Procida); 107400.0016). Some of the rare deficiency alleles have been found in Japanese (e.g., Pi S(Iiyama); 107400.0039).
Null AAT alleles are rare but have been found in all populations. Garver et al. (1986) investigated the molecular basis of the Pi null-null AAT phenotype. The gene appeared to be intact without discernible deletion or other structural abnormality, yet there was no detectable mRNA produced. The 5-prime promoter region also appeared to be normal. No evidence of hypermethylation of cytosine nucleotides in the promoter region was detected. The defect may be comparable to that in some forms of thalassemia in which a change, at a splicing site, for example, may lead to greatly reduced mRNA production. The null-null phenotype is accompanied by emphysema as is the ZZ and SZ phenotypes but an important difference is that cirrhosis and liver disease do not occur with the null-null phenotype; there is no abnormal antitrypsin produced that is excreted with difficulty from the cells of synthesis.
Nukiwa et al. (1987) identified a null form of alpha-1-antitrypsin resulting from a frameshift causing a stop codon to be formed approximately 44% from the N terminus of the precursor protein (Null(Granite Falls); 107400.0020). Although the molecular basis of antitrypsin deficiency was quite different from that in the Z haplotype, the phenotypic consequences were similar: severe deficiency associated with high risk of emphysema.
Seixas et al. (2002) reported 2 null alleles of the PI gene in Portuguese patients with emphysema. These alleles were associated with total lack of circulating protein as indicated by the absence of isoelectric focusing banding patterns. One of the alleles, designated Q0(Ourem), was identical to Q0(Mattawa) on an M3 normal background (107400.0022). The second allele, Q0(Porto), had a novel mutation which restricted mononuclear phagocyte transcripts to mRNA species resulting from the direct splice of exon IA to exon II. The absence of this normal splice alternative in the liver, where PI is primarily synthesized, provided a basis for the pathogenic effects of this mutation.
PI Pittsburgh
The PI Pittsburgh allele (met358-to-arg; 107400.0026), which occurs at the AAT active site, is an example of a mutation leading to altered function of the gene product. AAT becomes a potent inhibitor of thrombin and factor XI rather than of elastase. The mutation results in a bleeding disorder (Lewis et al., 1978; Owen et al., 1983).
SERPINA1 Haplotypes Associated with Chronic Obstructive Pulmonary Disease
While cigarette smoking is a major cause of COPD (see 606963), only 15% of smokers develop the disease, indicating major genetic influences. The most widely recognized candidate gene in COPD is SERPINA1, although it has been suggested that SERPINA3 (107280) 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.
DeCroo et al. (1991) studied the frequency of alpha-1-antitrypsin alleles in US whites, US blacks, and African blacks (living in Nigeria). While the PI*S allele was present at a polymorphic level in US whites, it was present only sporadically in US blacks and completely absent in African blacks. The PI*Z allele was not detected in the black populations tested. DeCroo et al. (1991) used the PI allele frequency data to calculate white admixture in US blacks. The average white admixture estimate in US blacks, based on all PI alleles, was about 13%. This value was about 24% when only the S and Z alleles were used.
Studies of the distribution of the S and Z alleles in Europe demonstrated that they occur mainly among those of European stock. Hutchison (1998) found that the frequency of the gene for PiZ is highest on the northwestern seaboard of the continent and that the mutation seems to have arisen in southern Scandinavia. The distribution of PiS is quite different: the gene frequency is highest in the Iberian peninsula and the mutation is likely to have arisen in that region.
By means of a metaanalysis of 43 studies, Blanco et al. (2001) analyzed the distribution of the PI*S and PI*Z alleles in countries outside Europe and compared them with data from Europe.
The pallid (pa) (604310) mouse develops emphysema late in life. Martorana et al. (1993) demonstrated that pallid mice have markedly reduced levels of serum alpha-1-antitrypsin associated with severe deficiency in serum elastase inhibitory capacity. However, they have normal alpha-1-antitrypsin mRNA levels in the liver.
Green et al. (2003) showed that Drosophila 'necrotic' (nec) mutations can mimic alpha-1-antitrypsin deficiency. They identified 2 nec mutations homologous to an antithrombin point mutation that is responsible for neonatal thrombosis. Transgenic flies carrying an amino acid substitution equivalent to that found in S(Iiyama) variant antitrypsin (107400.0039) failed to complement nec-null mutations and demonstrated a dominant temperature-dependent inactivation of the wildtype nec allele. Green et al. (2003) concluded that the Drosophila nec system can be used as a powerful system to study serpin polymerization in vivo.
Van Pel et al. (2006) reported that IL8 (146930)- and GCSF (CSF3; 138970)-induced mobilization of hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) in mice was completely inhibited by total body irradiation (TBI). They found that TBI increased expression of Serpina1 mRNA and protein, which inhibited elastase activity. Inhibition of HSC/HPC mobilization in irradiated mice could be reversed by anti-Serpina1. Furthermore, injection of Serpina1, but not heat-inactivated Serpina1, prior to administration of IL8 inhibited HSC/HPC mobilization. Van Pel et al. (2006) concluded that low-dose TBI induces Serpina1 in bone marrow and inhibits HSC/HPC mobilization, and they hypothesized that cytokine-induced HSC/HPC mobilization is determined by a critical balance between serine proteases and their inhibitors.
Kamimoto et al. (2006) bred the PiZ mouse onto the GFP-LC3 background to monitor autophagy.
Hidvegi et al. (2010) demonstrated that the autophagy-enhancing drug carbamazepine decreased the hepatic load of mutant alpha-1-antitrypsin Z (ATZ) protein and hepatic fibrosis in a mouse model of AAT deficiency-associated liver disease. The mouse used was the PiZ mouse, developed by Dycaico et al. (1988), in which the human ATZ gene is a transgene. Although the PiZ mouse has normal circulating levels of endogenous murine alpha-1-antitrypsin, it is a robust model of liver disease associated with AAT deficiency, as characterized by intrahepatocytic ATZ-containing globules, inflammation, and increased regenerative activity, dysplasia, and fibrosis. Hidvegi et al. (2010) concluded that their results in this animal model provided a basis for testing carbamazepine, which has an extensive clinical safety profile in patients with AAT deficiency (613490) and also provided proof of principle for therapeutic use of autophagy enhancers.
The polymorphism of prealbumin described by Fagerhol and Braend (1965) was shown by Fagerhol and Laurell (1967) to be the same as the alpha-1-antitrypsin polymorphism.
A possible heterogeneity in recombination frequency between Pi variants believed to be allelic was reported by Gedde-Dahl et al. (1972): Pi(Z) had less recombination with Gm than Pi(non-Z). Gedde-Dahl et al. (1975) gave further data on the Gm-Pi linkage. They considered heterogeneity of recombination fraction among males of different Pi types to be likely. The major difference seemed to be between the Pi(Z) and other alleles. Possible explanations included a chromosomal deletion, inversion or locus regulating recombination in linkage disequilibrium with the Pi locus. Gedde-Dahl et al. (1981) showed that the allele-specific heterogeneity of Gm-Pi linkage is attributable to 'reduced' recombination in Z-allele heterozygotes. They found an equal sex ratio for Pi 'non-Z' variants, as opposed to a 1:2 male-female ratio for 'Z' families. The location of Gm and Pi on 6p was excluded by Bender et al. (1979).
Babron et al. (1990) confirmed a previous finding that the presence of the Pi Z allele tends to decrease the recombination rate between the GM (147100) and PI loci. This decrease appeared to be similar in both sexes and not unique in males as previously noted. The results suggested a possible linkage disequilibrium between the Pi Z allele and a large inversion between the GM and PI loci.
Carrell (1986) cited evidence for the existence of 2 genes coding for alpha-1-antitrypsin, although the plasma findings were compatible with expression of the alleles at a single locus.
M1A, a normal variant, is believed to be the 'oldest' human PI allele, with the other common normal alleles M1V (107400.0002), M2 (107400.0003), and M3 (107400.0004) derived from M1A by single base substitutions. M2 is derived from M3; it has the same amino acid difference that distinguishes M3 from M1V but a second substitution in addition. The 4 common normal alleles are considered the 'base' from which all the other alleles are derived (see Fig. 4 in Crystal, 1989). The M1A allele has a frequency of 0.20-0.23 in US Caucasians.
This normal allele has a frequency of 0.44-0.49 in US Caucasians.
M2, which has a frequency of 0.10-0.11 in US Caucasians (Cox, 1989), was studied by Nukiwa et al. (1988), who found that its coding exons are identical to those of the more frequent form of M1 (val213) except for 2 bases: a change in codon 101 from CGT to CAT, leading to an amino acid change of arginine to histidine; and a change in codon 376 from GAA to GAC, resulting in an amino acid change from glutamic acid to aspartic acid. Since 2 mutations separate these 2 common alleles, Nukiwa et al. (1988) suggested that another AAT variant (presumably M3) was an intermediate in their evolution.
This normal variant allele has a frequency of 0.14-0.19 among US Caucasians. Graham et al. (1990) identified a single nucleotide difference between M1 (val213) and M3: a transversion in codon 376 from GAA(glu) to GAC(asp).
M4, an uncommon normal allele, is likely derived by single substitution from M1V; however, it has the same mutation that changed M2 to M3, and thus it is possible that M4 derived from M3 (or vice versa).
Yoshida et al. (1979) found 2 amino acid substitutions in the rare antitrypsin variant PiB Alhambra. One substitution was asp for lys at an unknown location (Crystal, 1989).
This rare 'normal' allele has a CGT-to-TGT change in codon 223 (Crystal, 1989; Okayama et al., 1991).
In addition to a GAC-to-AAC change in codon 341, this rare 'normal' allele has a 'silent' asp256 (GAT)-to-asp256 (GAC) change. The rare P-family of AAT variants is defined by the position of migration of the protein on isoelectric focusing (IEF) of serum between the common M and S variants. The P(St. Albans) allele is associated with normal serum levels of AAT, whereas the P(Lowell) allele (107400.0019) is associated with reduced levels. Holmes et al. (1990) described the DNA change underlying both of these variants.
This rare 'normal' allele has been sequenced only at the level of the protein (Crystal, 1989).
Brennan and Carrell (1986) characterized antitrypsin Christchurch, which shows a substitution of lysine for glutamic acid at position 363. Although electrophoretic mobility of the mutant protein was abnormal, no functional abnormality of the protein was detected. The base PI allele, M1A or M1V, is unknown (Crystal, 1989).
This is the most frequent allele leading to a high risk of emphysema (and liver disease) in the homozygote; the allele frequency is 0.01-0.02 in US Caucasians (Crystal, 1989). Nukiwa et al. (1986) demonstrated the val213-to-ala substitution (here symbolized M1A) in PI*Z in addition to the disease-producing glu342-to-lys mutation. Ala213 was found in all of 40 Z haplotypes, using synthetic oligonucleotide gene probes directed toward the mutated exon 3 sequences in the Z gene. Furthermore, the exon 3 mutation eliminated a BstEII restriction endonuclease site, allowing rapid identification of the change in genomic DNA. Surprisingly, only 23% of the M1 haplotypes were found to be BstEII site negative. The new form of M1, i.e., M1(ala213), is identical to M1 but has an isoelectric focusing 'silent' amino acid substitution. M1 has a frequency of 68 to 76%; M2, 14 to 20%; and M3, 10 to 12%. The Z gene represents 1 to 2% of all alpha-1-antitrypsin haplotypes.
Using 2 genomic probes extending into the 5-prime and 3-prime flanking regions, respectively, Cox et al. (1985) identified 8 polymorphic restriction sites for the PI gene. Extensive linkage disequilibrium was found with the PI Z allele throughout the probe region, but not with the normal PI M allele. The Z allele occurred mainly with one haplotype, indicating a single, relatively recent origin in Caucasians. This was an individual who lived in northern Europe some 6,000 years ago. Since then, the variant has spread through Europe with a frequency gradient extending from north to south: 5% of Scandinavians, 4% of Britons, 1 to 2% of southern Europeans, and 3% of the heterogeneous white population in the United States are MZ heterozygotes. Curiously, there is a reciprocal distribution of the S variant form: 10% in southern Europe to 5% in the north. As a general rule then, 1 in 10 persons of European origin will be heterozygous for either the S or Z variant, i.e., MZ or MS (Carrell, 1986). Kawakami et al. (1981) cited 2 studies in which no Pi Z was found among 965 healthy Japanese and 183 Japanese with pulmonary diseases. This is to be compared with a frequency of 1.6% for Pi Z among Norwegians.
Crystallographic analysis of alpha-1-antitrypsin predicts that in the normal protein a negatively charged glu342 is adjacent to a positively charged lys290. Thus, the glu342-to-lys Z mutation causes the loss of a normal salt bridge, resulting in intracellular aggregation of the Z molecule. Brantly et al. (1988) predicted that a second mutation that changed the positively charged lys290 to a negatively charged glu290 would correct the secretion defect. They demonstrated that such was the case: when the second mutation was added to the Z-type cDNA, the resulting gene directed the synthesis and secretion of AAT similar to that directed by the normal AAT cDNA in an in vitro eukaryotic expression system. In general it may be possible to correct human hereditary disease by inserting an additional mutation in the gene.
By analyzing nonrecombinant SNPs of 21 Latvian and 65 Swedish heterozygous and homozygous PI Z allele carriers and 113 healthy Latvian controls, Lace et al. (2008) estimated the age of the PI Z mutation to be 2,902 years in Latvia and 2,362 years in Sweden. The SNPs showed a high degree of similarity between the 2 populations, indicating a common ancestor.
Approximately 3 to 5% of patients with cystic fibrosis (CF; 219700) develop severe liver disease defined as cirrhosis with portal hypertension. Bartlett et al. (2009) performed a 2-stage case control study enrolling patients with CF and severe liver disease with portal hypertension from 63 CF centers in the United States as well as 32 in Canada and 18 outside of North America. In the first stage, 124 patients with CF and severe liver disease, enrolled between January 1999 and December 2004, and 843 control patients without CF-related liver disease (all assessed at greater than 15 years of age) were studied by genotyping 9 polymorphisms in 5 genes previously studied as modifiers of liver disease in CF. In the second stage, the 2 genes that were positive from the first stage were tested in an additional 136 patients with CF-related liver disease enrolled between January 2005 and February 2007, and in 1,088 with no CF-related liver disease. The combined analysis of the initial and replication studies by logistic regression showed CF-related liver disease to be associated with the SERPINA1 Z allele (odds ratio = 5.04; 95% confidence interval 2.88-8.83; p = 1.5 x 10(-8)). Bartlett et al. (2009) concluded that the SERPINA1 Z allele is a risk factor for liver disease in CF. Patients carrying the Z allele are at greater risk (odds ratio = approximately 5) of developing severe liver disease with portal hypertension.
Using several markers of ER stress response, Kelly et al. (2009) found that expression of AAT with the Z mutation, which they called ZAAT, resulted in ER stress in transfected HepG2 cells. Coexpression of the ER stress response selenoprotein SEPS1 (607918) relieved ER stress caused by ZAAT expression or by exposure to tunicamycin, a known ER stressor. Supplementation of cells with selenium augmented the activity of SEPS1. Selenium supplementation also increased endogenous SEPS1 expression and reduced ER stress.
Using AT01 human liver cells overexpressing GP78, Khodayari et al. (2017) showed that GP78 (AMFR; 603243) regulated degradation of ubiquitinated ZAAT. GP78 targeted ZAAT for proteasomal degradation, and GP78 overexpression significantly decreased the level of accumulated ZAAT and caused faster ZAAT clearance from the ER, without significant changes in the level of extracellular ZAAT. This process involved VCP (601023), as GP78 interacted with VCP, and the interaction was enhanced in A1ATD liver tissue. SVIP (620965) expression was relatively high in A1ATD, and overexpression of SVIP negatively regulated GP78/VCP-mediated ERAD. Knockdown analysis in AT01 cells confirmed that endogenous SVIP negatively regulated GP78 function and inhibited ZAAT degradation. Electron microscopic analysis revealed that SVIP overexpression caused vacuole formation in AT01 cells, which was abrogated by silencing of SVIP. The authors proposed that GP78 overexpression or SVIP suppression may eliminate the toxic gain of function associated with ZAAT polymerization, thus providing a novel therapeutic approach to treatment of A1ATD.
Liver disease, as well as emphysema, has been described in patients with the rare PI*M(Malton) allele. Fraizer et al. (1989) studied the molecular defect in M(Malton), a deficiency allele which, like the Z allele, is associated with hepatocyte inclusions and impairs secretion. They found that the M(Malton) allele contains a deletion of the codon for 1 of the 2 adjacent phenylalanine residues (amino acid 51 or 52 of the mature protein). Judging from the haplotype data, the M(Malton) mutation must have derived from the normal M2 allele. Deletion of the 1 amino acid would be expected to shorten 1 strand of the beta-sheet, B6, apparently preventing normal processing and secretion. Curiel et al. (1989) also showed that the M(Malton) allele differs from the normal M2 allele by deletion of the entire codon (TTC) for residue phe52. They demonstrated abnormal intracellular accumulation of newly synthesized AAT protein in a homozygote who also showed, on liver biopsy, inflammation, mild fibrosis, and intrahepatocyte accumulation of the protein. Furthermore, Curiel et al. (1989) showed by retroviral gene transfer of AAT cDNA with the M(Malton) phe52 deletion into murine cells that abnormal accumulation of the newly synthesized protein occurred. This provides further evidence that abnormal intrahepatocyte AAT accumulation is responsible for the liver injury. By means of gene amplification and direct DNA sequencing, Graham et al. (1989) identified the same mutation, pointing out that it could be either phenylalanine-51 or phenylalanine-52 that is deleted.
Owen and Carrell (1976) and Yoshida et al. (1977) found substitution of valine for glutamic acid at position 264 in the S variant of alpha-1-antitrypsin. See Long et al. (1984).
Curiel et al. (1989) concluded that the S-type AAT protein is degraded intracellularly before secretion. PI*S homozygotes are at no risk of emphysema, but compound heterozygotes with Z or a null allele have a mildly increased risk. Because of the high frequency of the PI*S allele (0.02-0.04 in US Caucasians), such compound heterozygotes are relatively frequent.
Hofker et al. (1989) demonstrated the molecular defect in the PI gene of a patient with a serum level of only 5 mg/100 ml and a PI M-like phenotype, designated PI M(Heerlen). They demonstrated a substitution of leucine for proline at codon 369, which resulted from a C-to-T mutation in exon 5. Otherwise the nucleotide sequence of the exons, intron/exon junctions, and a part of the promoter region was similar to that of a PI M1(ala213) gene. Kalsheker et al. (1992) described a family with Pi M(Heerlen) and commented on the difficulties of diagnosis of rare PI (null) or Q0 variants.
This mutation, which causes AAT deficiency and emphysema, is unique among antitrypsin mutations in that it was observed in a black family, whereas most mutations causing AAT deficiency are confined to Caucasian populations of European descent. The index case was homozygous. A GGG-to-GAG change in codon 67 led to substitution of glutamic acid for glycine (Curiel et al., 1990). Curiel et al. (1990) showed that this mutation caused reduced AAT secretion on the basis of aberrant posttranslational biosynthesis by a mechanism distinct from that associated with the Z allele, whereby intracellular aggregation of the mutant protein is responsible for the secretory defect. Furthermore, the M(Mineral Springs) mutation markedly affected the ability of the protein that did reach the circulation to inhibit neutrophil elastase. Homozygotes have a high risk of emphysema (Crystal, 1989).
Takahashi et al. (1988) showed that M(Procida) has a substitution of proline for leucine at position 41, resulting from a change of codon CTG to CCG. The rare mutant protein shows somewhat reduced catalytic activity; its concentration is low in plasma, apparently because of instability and resulting intracellular degradation before secretion. Homozygotes have a high risk of emphysema (Crystal, 1989).
Nakamura et al. (1980) found this variant in a 42-year-old Japanese woman with neither pulmonary emphysema nor liver dysfunction. She was the product of a consanguineous marriage. Radial immunodiffusion assay showed a low level of AAT in serum (17.9 mg/dl as compared to the normal range of 190-280 mg/dl). Aggregation of AAT molecules was demonstrated histologically in hepatocytes, indicating profound reduction in the secretion of the protein. Serum AAT levels in the members of the family demonstrated that the proband was homozygous for the M(Nichinan) allele. Matsunaga et al. (1990) demonstrated that the M(Nichinan) gene is identical with the M1(val213) gene except for 2 changes: a TTC trinucleotide deletion in the codon for phenylalanine-52 and a G-A substitution by which the normal gly148(GGG) became arg148(AGG). Matsunaga et al. (1990) suggested that the gly148-to-arg change is unlikely to be the cause of the AAT deficiency because arg (not gly) is located at the corresponding position of the protein C inhibitor which belongs to the same family of serine protease. On the other hand, Matsunaga et al. (1990) suggested that deletion of phenylalanine-52 may cause the newly synthesized AAT protein to aggregate, resulting in serum AAT deficiency. They suggested that the gly148-to-arg substitution reflects the vulnerability of a CpG dinucleotide to mutation. They pointed to a number of other variant forms of AAT that were probably generated through a C-T transition. Indeed, the Z and M1(val213) genes were generated from the M1(ala213) gene by the C-T transition at the CpG dinucleotide on the antisense and the sense strands, respectively. The M2 gene was generated from the M3 gene by the same mechanism.
By gene amplification and direct DNA sequencing, Graham et al. (1989) identified this mutation, CGC to TGC, in a compound heterozygote. Homozygotes are at no risk of emphysema, but compound heterozygotes with Z or a null allele have a mildly increased risk (Crystal, 1989). In 1 individual and 3 independent families, Seri et al. (1992) confirmed that the I variant resulted from a CGC (arg)-to-TGC (cys) transition at codon 39 within exon 2.
Faber et al. (1989) demonstrated that this rare allele, a cause of deficiency of alpha-1-antitrypsin, results from an A-to-T transversion in exon 3 of the gene. As a result, GAT (aspartic acid at residue 256) is converted to GTT (valine at that position). The same change was found in a total of 4 families.
By gene amplification and direct DNA sequencing, Graham et al. (1989) identified the same mutation in a variant they called Null(Cardiff). According to the tabulation by Crystal (1989), homozygotes have no risk for emphysema, but compound heterozygotes with a Z or null allele have a mildly increased risk.
By retroviral insertion of the P(Lowell) cDNA into the genome of NIH-3T3 fibroblasts, Holmes et al. (1990) demonstrated a pattern of biosynthesis of AAT consistent with the intracellular degradation of newly synthesized protein. Because serum AAT deficiency associated with other mutations resulting from intracellular degradation of the protein can be overcome by administration of estrogenlike drugs, Holmes et al. (1990) administered tamoxifen to a subject with the P(Lowell)/Z phenotype and demonstrated a 48% rise in AAT serum levels over a 5-month period, from below the threshold for protection from emphysema to a value above that threshold. Seri et al. (1992) confirmed the nature of the mutation in P(Lowell).
Hildesheim et al. (1993) demonstrated that P(Duarte) (107400.0037) has the same mutation as that in P(Lowell) but that it is on a background of the normal M4 allele (R101H; 107400.0005). Hildesheim et al. (1993) pointed out that this is an example of genetic diversity resulting from a limited repertoire of mutations on different common allelic backgrounds--a combinatorial basis for genetic diversity. A similar example is the occurrence of Creutzfeldt-Jakob disease and fatal familial insomnia as a result of the same mutation, depending on the nature of a nucleotide polymorphism at another site in the prion protein gene (PRNP; 176640.0010).
The gene shows deletion of the third nucleotide in the tyr160 codon TAC, causing a frameshift with new stop codon TAG at position 160 (Nukiwa et al., 1987). Emphysema is associated with homozygosity.
By cloning and sequencing the Null(Bellingham) gene (which in homozygous state is associated with early-onset emphysema), Satoh et al. (1988) demonstrated that the promoter region, coding exons, and all exon-intron junctions are normal except for a single base substitution in exon 3, which causes the normal lys217 (AAG) to become a stop codon (TAG).
Cox and Levison (1988) reported a family in which several members manifested no detectable plasma alpha-1-antitrypsin (613490), indicating a 'null' AAT allele, which the authors designated Null Mattawa (QO-Mattawa). Curiel et al. (1989) studied 2 affected sisters in this family and found that they were compound heterozygous for 2 mutations in the AAT gene: Null(Bellingham) (107400.0021) and Null(Mattawa). Sequencing of exons 1c-5 and all exon-intron junctions of the Null(Mattawa) gene demonstrated that it was identical to the common normal M1(val213) gene except for the insertion of a single nucleotide within the coding region of exon 5, causing a 3-prime frameshift with generation of a premature stop signal at position 376. Monocytes were shown to have an mRNA transcript of normal size, and in vitro translation showed that the mRNA was translated at a normal rate but produced a truncated antitrypsin protein. Additionally, retroviral transfer of the cDNA to murine fibroblasts demonstrated no detectable intracellular or secreted protein despite the presence of Null(Mattawa) mRNA. Thus, the molecular pathophysiology of Null(Mattawa) is probably manifested at a posttranslational level. This allele is associated with high risk of emphysema.
Of the 5 previously known representatives of the 'null' group of AAT-deficient alleles (i.e., genes incapable of producing AAT protein detectable in serum) evaluated at the gene level, all had stop codons in coding exons. Cloning and mapping of the Null(Isola di Procida) gene demonstrated deletion of a 17-kb fragment that included exons 2-5 of the AAT structural gene (Takahashi and Crystal, 1990). Sequence analysis showed a 7-bp repeat sequence both 5-prime to the deletion and at the 3-prime end of the deletion, suggesting that the mechanism of the deletion may have been a slipped mispairing. This mutation, which at first was called Null(Procida), was found in heterozygous state with the M(Procida) allele (107400.0016) reported by Takahashi et al. (1988). To avoid confusion with M(Procida), Null(Procida) was renamed Null(Isola di Procida). This mutation is associated with high risk of emphysema.
Deletion of TC from CTC codon 318 for leucine causes frameshift with stop codon TAA at position 334. Homozygosity for this allele, like other null alleles, predisposes to early-onset emphysema. See Sifers et al. (1988). This variant was initially called Null(Hong Kong) but later Null(Hong Kong-1) because a second null allele called Null(Hong Kong-2) (107400.0034) was identified in the same individual by haplotype analysis (Fraizer et al., 1990).
Fraizer et al. (1989) observed a unique PI null allele. By cloning and sequencing the allele, they demonstrated deletion of a single cytosine residue (the third C in the CCC codon 362 for proline) near the active site of alpha-1-antitrypsin in exon 5 resulting in a frameshift which caused an in-frame stop codon downstream of the deletion. The stop codon led to premature termination of protein translation at amino acid 373, resulting in a truncated protein. PI Q0(Bolton) was observed in combination with PI*M(Malton) in 2 compound heterozygotes. The allele carries a high risk of emphysema.
This structure mutation in the PI gene alters its function such that it becomes an antithrombin and leads to a bleeding disorder. Alpha-1-antitrypsin and antithrombin III (107300) have a similar structure reflecting origin from a common ancestral protein some 500 million years ago. Both are inhibitors of proteolytic enzymes but have different specificities. Alpha-1-antitrypsin protects the body against released elastase, whereas AT III controls coagulation by inhibiting thrombin and other activated coagulation factors. Owen et al. (1983) described a mutation of alpha-1-antitrypsin that converts it to an antithrombin. Whereas synthesis of alpha-1-antitrypsin increases in response to trauma, AT III remains at a constant plasma concentration and requires activation by heparin. The antithrombin activity of the mutant alpha-1-antitrypsin was independent of heparin but its synthesis was stimulated by trauma. The patient was a 14-year-old boy who died in 1981 with a huge hematoma of his leg and abdomen. This was the last of a lifelong series of bleeding episodes occurring after trauma and requiring hospitalization on more than 50 occasions. Lewis et al. (1978) described the clinical picture and identified a variant 'antithrombin' which they called antithrombin Pittsburgh. It had, however, the electrophoretic and antigenic characteristics of a variant alpha-1-antitrypsin. Owen et al. (1983) showed that the variant protein has arginine at position 358, replacing the normal methionine. This finding indicated that the reactive center of alpha-1-antitrypsin is methionine 358, which acts as a 'bait' for elastase, just as the normal reactive center of AT III is arginine-393, which acts as a bait for thrombin. Neutrophils augment tissue proteolysis by the oxidative inactivation of the methionine at the reactive center of alpha-1-antitrypsin. Scott et al. (1986) and Schapira et al. (1986) found that recombinant AAT-Pittsburgh (met358-to-arg) is a potent inhibitor of plasma kallikrein and activated factor XII fragment, although it has lost its anti-elastase activity. They suggested it might have therapeutic potential in hereditary angioedema or septic shock. Vidaud et al. (1992) demonstrated that a G-to-T transversion at nucleotide 10038 is responsible for the substitution of arg for met, which converts alpha-1-antitrypsin into an arg-ser protease inhibitor (serpin) that inhibits thrombin and factor Xa more effectively than antithrombin III. They observed a 15-year-old boy who surprisingly had no bleeding history. They suggested that a large decrease in protein C concentration may account for the mild or absent bleeding tendency. The deficiency of protein C in turn was attributed to deleterious effect of the abnormal inhibitor on both intracellular processing and catabolism of protein C. In later studies, Emmerich et al. (1995) suggested that strong affinity of the mutant AAT for protein C leads in the patient of Vidaud et al. (1992) to an increased turnover and thus to a low circulating level of protein C. They proposed that in the presence of the Pittsburgh mutant protein C can be activated and is abnormally rapidly cleared. The resultant relative lack of protein C anticoagulant function may ameliorate the bleeding diathesis expected to be associated with the Pittsburgh mutation.
Wilkie (1994) discussed the molecular basis of genetic dominance and provided a useful table. He indicated altered substrate specificity as one mechanism and antithrombin Pittsburgh as a specific example.
In an alpha-1-antitrypsin variant called V(Munich) because the major fraction focused in the 'V' region of the isoelectric focusing gel, Holmes et al. (1990) found that the molecule differs from that of the common M1V allele by a single nucleotide substitution of cytosine for adenosine, with the resultant amino acid change asp2 to ala; the codon change is GAT to GCT.
Using isoelectric focusing with a narrow pH gradient, Weidinger et al. (1985) recognized a rare deficient PI variant, which they called PI Z(Augsburg). To their surprise, Faber et al. (1990) found that the sequence of the Z(Augsburg) gene showed the common PI*Z mutation (M1 glu342 GAG to Z lys342 AAG) which occurred, however, in an M2 ancestral gene. Previous findings indicated that the Z mutation had always been derived from an M1 ala213 background gene. Whitehouse et al. (1989) studied 2 sibs with mild liver abnormality who were found to be compound heterozygotes for the classical PI*Z allele and an allele that they called PI*Z(Tun). The Z(Tun) protein appeared to be deficient in the plasma to about the same degree as the Z protein. They found that the mutation was precisely the same as that in the Z allele, namely, a G-to-A transition at codon 342 resulting in the substitution of lysine for glutamic acid; however, the Z(Tun) mutation had occurred on an M2-like haplotype background rather than the M1A background. Because of its association with a unique DNA haplotype and the gene frequency estimates in populations of European origin, the Z mutation is thought to have occurred only once, about 6,000 years ago, in a North European person. The Z gene is very rare among other ethnic groups.
This variant allele, which is associated with increased risk of emphysema and liver disease, has a mutation in exon 5 where codon 336 is changed from GCT to ACT, resulting in substitution of threonine for alanine (Crystal, 1990). Holmes et al. (1990) reported that the W(Bethesda) form differs from the normal M1(ala-213) allele by a change in codon 336 from GCT to ACT. Although W(Bethesda) mRNA was translated normally in vitro, transfection of the W(Bethesda) cDNA into COS-I cells was associated with AAT secretion only 50% that of cells transfected with normal cDNA. There was no intracellular accumulation as observed with the Z allele, but reduced intracellular AAT suggested degradation of newly synthesized W(Bethesda) molecules.
This variant, which is associated with increased risk of emphysema and liver disease, is due to a change in exon 2, resulting in substitution of serine for glycine-115 (Crystal, 1990). In a compound heterozygote carrying the common disease-producing mutation Pi Z (107400.0011), Graham et al. (1990) found a substitution of glycine-115 by serine. The mutation occurred on the background of M3. A change in codon 115 from GGC to AGC was responsible.
In this variant, which is associated with increased risk of emphysema and liver disease, a change in codon 92 from ATC to AAC in exon 2 results in substitution of asparagine for isoleucine (Crystal, 1990). This substitution of a polar for a nonpolar amino acid occurs in 1 of the alpha-helices and is predicted to disrupt the tertiary structure (Fraizer et al., 1990). Fraizer et al. (1990) identified a T-to-A substitution in a German patient.
In a compound heterozygote with the common disease-producing PI Z mutation (107400.0011), Graham et al. (1990) found a change from TCG to TTG in codon -19, which resulted in a change from serine to leucine in the signal peptide.
See 107400.0024 and Fraizer et al. (1990).
Poller et al. (1991) found complete deletion of the AAT gene as the basis for PI Q0(Riedenburg). The deletion extended into the 3-prime flanking region of the gene but did not include the noncoding AAT-related gene (PIL), which is located 12 kb downstream of AAT (Hofker et al., 1988).
Kalsheker et al. (1987) and Poller et al. (1990) reported a mutation in the 3-prime flanking sequence of the AAT gene that occurs in about 17% of patients with chronic respiratory disease. The mutation is a G-to-A nucleotide substitution in an octamer (OCT)-like sequence. Because TCGA is converted to TCAA, the mutation is detected as a restriction fragment length polymorphism with the restriction enzyme TaqI. The mutation does not appear to affect basal expression of the protein as the plasma concentration of alpha-1-antitrypsin is normal in persons who carry the mutation; however, binding and functional studies by Morgan et al. (1993) suggested that it may reduce the rise in plasma AAT concentration that occurs during inflammation. Stimulation by cytokines, such as interleukin-6 (IL6; 147620), may be lacking. Morgan et al. (1993) pointed out a precedent for such a mechanism in an unrelated gene: an enhancer element in the 3-prime flanking sequence of the erythropoietin gene increases gene expression nearly 15-fold during hypoxia.
Hildesheim et al. (1993) demonstrated that the deficiency-producing change in the PI gene in P(Duarte) is the same as that in P(Lowell) (107400.0019). The alleles differ with respect to polymorphic nucleotides at other positions in the gene. They referred to this as genetic diversity from a limited repertoire of mutations on different common allelic backgrounds.
During routine screening of individuals applying for enrollment in the US AAT Deficiency Registry, Laubach et al. (1993) identified a patient with emphysema and a PI type heterozygous for a novel AAT null allele. The novel allele, designated PI*Q0(West), was characterized by a single G-to-T transversion at position 1 of intron 2, a highly conserved nucleotide position. This resulted in an in-frame deletion of amino acids gly164-to-lys191. This was the first splicing mutation observed in the AAT gene.
In a 32-year-old Japanese male with pulmonary emphysema, Yuasa et al. (1993) demonstrated homozygosity for a C-to-T transition at codon 53 resulting in substitution of phenylalanine for serine. They commented on the fact that, in Japanese, deficiency in null alleles at the AAT locus are extremely rare and PI*Z, which occurs at polymorphic frequencies in Caucasians, has not been reported. The only other Japanese case of AAT deficiency was that due to PI M(Nichinan) (107400.0017) reported by Matsunaga et al. (1990).
In a woman with an obstetric history of 3 perinatal deaths from fulminant liver disease and no living offspring, Lovegrove et al. (1997) found that she and her father were both heterozygotes for PI M1Z(Bristol). The Z(Bristol) protein was found to be active as a proteinase inhibitor but appeared to be deficient in the plasma to about the same degree as the S protein in MS heterozygotes. It focused on the basic side of Z and lacked the normal pattern of secondary isoforms associated with the commonly occurring AAT variants and migrated faster than normal on an SDS electrophoresis gel. The Z(Bristol) mutation was found to be a C-to-T transition at codon 85, changing ACG (thr) to ATG (met). This disrupted the N-glycosylation site starting at asn83, preventing glycosylation at residue 83 in the PI Z(Bristol) protein, and explained the protein isoelectric focusing and SDS gel electrophoresis results. An analysis of haplotypes in the propositus and her father indicated that the Z(Bristol) mutation occurred on the common M1(val213) genetic background. Of the 3 offspring with perinatal death from fulminant liver disease, 2 were by the woman's husband and 1 by an artificial insemination donor. Of the 2 offspring who were tested for the mutation, 1 had the variant and the other did not. Thus, the relationship between Z(Bristol) and fulminant liver disease in the offspring was unclear.
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