Alpha-1-Antitrypsin Deficiency


A number sign (#) is used with this entry because alpha-1-antitrypsin deficiency is caused by mutation in the SERPINA1 gene (107400), most often by homozygosity for the PiZ allele (107400.0011).


Alpha-1-antitrypsin deficiency is an autosomal recessive disorder. The most common manifestation is emphysema, which becomes evident by the third to fourth decade. A less common manifestation of the deficiency is liver disease, which occurs in children and adults, and may result in cirrhosis and liver failure. Environmental factors, particularly cigarette smoking, greatly increase the risk of emphysema at an earlier age (Crystal, 1990).

Clinical Features

Laurell and Eriksson (1963) described absence of alpha-1-antitrypsin from the plasma in patients with degenerative lung disease leading to death in middle life. Emphysematous changes involve primarily the lower lung fields (Bell, 1970).

Gans et al. (1969) described familial infantile liver cirrhosis in presumed homozygotes for alpha-1-antitrypsin deficiency.

An adult with antitrypsin deficiency and combined liver and lung disease was reported by Gherardi (1971). See the study of 12 cases of combined disease by Berg and Eriksson (1972).

Aagenaes et al. (1972) described the clinical picture in children with severe AAT deficiency (ZZ genotype) as neonatal cholestasis. Five such cases were described.

Fargion et al. (1981) found an increased frequency of non-M phenotypes in patients with hepatocellular carcinoma. Furthermore, patients with liver cancer and a non-M phenotype had a lower average age than those with an M phenotype.

Cox and Smyth (1983) found a relatively high risk for liver disease in men between 51 and 60 years who had AAT deficiency. A low concentration of serum prealbumin was a sensitive indicator of impaired liver function.

Eriksson et al. (1986) concluded that the risk of cirrhosis and liver cancer is increased for males homozygous for alpha-1-antitrypsin deficiency but not for females. The finding suggested additive effects of exogenous factors.

Wiebicke et al. (1996) confirmed the absence of pulmonary function abnormalities in the vast majority of children with severe (homozygous ZZ) AAT deficiency.

Rodriguez-Cintron et al. (1995) suggested that bronchiectasis should be considered part of the spectrum of pulmonary pathology that may be encountered in individuals with AAT deficiency. They described a 21-year-old man with massive hemoptysis and severe (homozygous ZZ) AAT deficiency. Neither panlobular emphysema nor cirrhosis of the liver was present.

Other Features

Morin et al. (1975) concluded that heterozygotes are not at increased risk of alcoholic cirrhosis.

Geddes et al. (1977) found that the frequency of non-M AAT phenotypes was increased to a significant extent in patients with sclerosing alveolitis with or without rheumatoid arthritis.

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.

Hendrick et al. (1988) described 3 patients in whom panniculitis was the presenting manifestation of AAT deficiency. Two were young adults and 1 was a child. The panniculitis in these cases is frequently, although not always, precipitated by trauma. The panniculitis is chronic, relapsing, and widely disseminated with new lesions appearing as old lesions resolve.

Fortin et al. (1991) reported a third incidence of systemic vasculitis associated with the ZZ genotype, which took the form of polyarteritis nodosa.

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 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. 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.


Kidd et al. (1983) used a chemically synthesized specific oligonucleotide probe (19-mer) as a sensitive and direct test for the presence or absence of the Z allele (E342K; 107400.0011). Kidd et al. (1984) reported the use of such probes in the prenatal diagnosis of the deficiency syndrome.

Hejtmancik et al. (1986) compared prenatal diagnosis by RFLP analysis with prenatal diagnosis by oligonucleotide probe analysis. They concluded that although it seems reasonable to use oligonucleotide analysis in families in which no sibs are available for comparison, in all other situations RFLP analysis is preferable because it is as accurate and reliable as oligonucleotide analysis and is technically easier.

Abbott et al. (1988) used the PCR for prenatal diagnosis of alpha-1-antitrypsin deficiency associated with the ZZ genotype.

To identify accurately the SZ phenotype at the DNA level, Nukiwa et al. (1986) prepared 19-mer synthetic oligonucleotide probes: 2 to show the M/S difference in exon 3, and 2 to show the M/Z difference in exon 5.

Harrison et al. (1990) described an improved method for detecting what they termed 'low Z expressor' phenotype in MZ heterozygotes. An obligate carrier mother who was being typed as part of a family study appeared to be a PI(M)/PI(null) heterozygote. By routine isoelectric focusing, she was typed as M, her affected child as Z, and her husband as MZ. Atypically low concentrations of circulating Z peptides were demonstrated by the improved method.

Dry (1991) described a method for detecting the single-base substitution in PiZ useful for same-day diagnosis of AAT deficiency in chorion villus samples.


Udall et al. (1982) speculated that a factor in the pathogenesis of infantile cirrhosis may be lack of protease inhibitor to counteract the effects of proteases that cross the intestinal barrier in the neonate. Lake-Bakaar and Dooley (1982) found that alpha-1-antitrypsin is an important proteolytic inhibitor in bile, thus providing support of the pathogenetic theory of Udall et al. (1982).

Weitz et al. (1992) demonstrated a correlation between plasma levels of elastase-specific fibrinopeptides and PI genotype. The levels of these peptides were highest in ZZ homozygotes and intermediate in MZ heterozygotes. This was interpreted as evidence that unopposed human neutrophil elastase (ELA2; 130130) is responsible for emphysema in patients with alpha-1-proteinase inhibitor deficiency.

Lomas et al. (1992) presented an explanation for the accumulation of insoluble intracellular inclusions in the ZZ homozygote. Only about 15% of the AAT protein is secreted in the plasma in ZZ homozygotes. The 85% that is not secreted accumulates in the endoplasmic reticulum (ER) of the hepatocyte; much of it is degraded but the remainder aggregates to form insoluble intracellular inclusions. About 10% of newborn ZZ homozygotes develop liver disease that often leads to fatal childhood cirrhosis. Lomas et al. (1992) demonstrated the molecular pathology underlying this accumulation and described how the Z mutation in antitrypsin results in a unique molecular interaction between the reactive center loop of one molecule and the gap in the A-sheet of another. This loop-sheet polymerization of Z antitrypsin occurs spontaneously at 37 degrees C and is completely blocked by the insertion of a specific peptide into the A-sheet of the antitrypsin molecule. The loop-sheet polymerization is concentration- and temperature-dependent. At times of stress, the formation of inclusions in the hepatocyte will likely overwhelm the degradative mechanisms. Antitrypsin is an acute phase protein and as such undergoes a manifold increase in association with temperature elevations during bouts of inflammation. Control of inflammation and pyrexia in ZZ homozygote infants is important. In the long-term, more specific interventions may be possible, e.g., the delivery to the hepatocyte of engineered loop peptides specific to alpha-1-antitrypsin.

Liver injury in individuals with the ZZ genotype presumably results from toxic effects of the abnormal AAT molecule accumulating within the endoplasmic reticulum of liver cells; however, only 12 to 15% of individuals with this genotype develop liver disease. Therefore, Wu et al. (1994) predicted that other genetic factors determine susceptibility to liver disease. To examine this hypothesis, they transduced skin fibroblasts from ZZ individuals with liver disease and from ZZ individuals without liver disease with amphotropic recombinant retroviral particles designed to express the mutant AAT*Z gene under direction of a constitutive viral promoter. Expression of the AAT gene was conferred on each fibroblast cell line. Compared to the same cell line transduced with the wildtype gene, there was selective intracellular accumulation of the mutant protein in each case. However, there was a marked delay in degradation of the mutant protein after it accumulated in the fibroblasts from ZZ individuals with liver disease ('susceptible hosts') as compared to those without liver disease ('protected hosts'). Appropriate disease controls showed that the lag in degradation in susceptible hosts is specific for the combination of the ZZ genotype and liver disease. Biochemical characteristics of the ATT*Z degradation in the protected hosts was found to be similar to those of a common ER degradation pathway previously described for T-cell receptor alpha subunits and asialoglycoprotein receptor subunits, therefore raising the possibility that the lag in degradation in the susceptible host is a defect in this common ER degradation pathway.

As reviewed by Lomas (1996), inclusions in the most frequent cause of antitrypsin deficiency, the Z mutation (glu342lys; 107400.0011), is accompanied by accumulation of protein in the endoplasmic reticulum of the liver. These hepatic inclusions in turn result from a protein-protein interaction between the reactive center loop of 1 molecule and the beta-pleated sheet of a second. This loop-sheet polymerization is the basis of deficiencies associated also with mutations of C1-inhibitor (606860), antithrombin III (107300), and alpha-1-antichymotrypsin (107280), all of which are serine proteinase inhibitors (serpins).

Sigsgaard et al. (1992) showed that in cotton workers the airborne concentration of respirable endotoxin was associated with byssinosis. Endotoxin might induce byssinosis through the release of biochemical mediators at the bronchoalveolar surface. Alpha-1-antitrypsin, which neutralizes enzymes released by granulocytes, might have a counteracting role. Sigsgaard et al. (1994) found that the MZ phenotype was associated with an increased prevalence of byssinosis compared with the MM phenotype: 3/8 (38%) and 25/187 (13%). An association between the MZ phenotype and familial allergy was also found, although the association was somewhat weaker.

Carrell and Lomas (2002) suggested that alpha-1-antitrypsin deficiency is a model for conformational diseases. These are disorders due to aberrant intermolecular aggregation of proteins. Furthermore, alpha-1-antitrypsin deficiency provides a prototype for the diseases associated with abnormalities of various serpins, known collectively as the serpinopathies. Knowledge of the shared underlying conformational mechanism of protein deposition in neuronal tissues greatly increased understanding of what had previously been a daunting collection of syndromes of neurodegeneration. These included encephalopathy with neuroserpin inclusion bodies (604218), the Lewy-body variant of Alzheimer disease (see 127750) with deposits of alpha-synuclein (163890), prion protein (176640) deposition in Creutzfeldt-Jakob disease (123400), tau protein associated with Pick bodies of frontotemporal dementia (Pick disease; 172700), and the inclusions of huntingtin (613004) in Huntington disease (143100).

Clinical Management

Wewers et al. (1987) reported on treatment of patients with alpha-1-antitrypsin deficiency with intravenous plasma-derived AAT once a week. Although granting that a completely rigorous study was impossible, the authors concluded that infusions of AAT are safe and can reverse the biochemical abnormalities in serum and lung fluid and, further, that lifetime avoidance of cigarette smoking together with such replacement may be a logical approach to long-term therapy.

George et al. (1984) tested the effectiveness of a genetically engineered met358-to-val mutant in the reactive center of AAT as an inhibitor of connective tissue breakdown in a model of inflammation. Degradation of basement membrane collagen was efficiently inhibited by a concentration of the mutant substance that was tenfold lower than that of the normal antitrypsin. George et al. (1984) suggested the possible use of this mutant in the prophylaxis of lung dysplasias, notably emphysema.

The liver represents an excellent organ for gene therapy since many genetic disorders result from deficiency of liver-specific gene products. Kay et al. (1992) demonstrated the autologous transplantation of canine hepatocytes transduced with a retroviral vector containing the human alpha-1-antitrypsin cDNA under transcriptional control of the cytomegalovirus promoter. At least 1 billion hepatocytes or 5% of the liver mass could be transplanted by the portal vasculature. Human alpha-1-antitrypsin was demonstrable in the serum of 2 dogs for 1 month. Although the serum levels of human AAT eventually fell due to inactivation of the cytomegalovirus promoter, PCR analysis demonstrated that a significant fraction of the transduced hepatocytes migrated to the liver and continued to survive in vivo.

As a model for gene therapy, Garver et al. (1987) used a retroviral vector to insert human alpha-1-antitrypsin cDNA into the genome of mouse fibroblasts. After demonstrating that the clone produced human antitrypsin after more than 100 population doublings in the absence of selection pressure, they transplanted the clone into the peritoneal cavities of nude mice. When the animals were evaluated 4 weeks later, human antitrypsin was detected in both sera and the epithelial surface of the lungs. Lemarchand et al. (1992) reported experiments supporting the feasibility of in vivo human gene transfer of recombinant human AAT cDNA to endothelial cells by means of replication-deficiency adenovirus vectors.

Song et al. (1998) described experiments in mice in which recombinant adeno-associated virus (AAV) vectors were used to transduce skeletal muscle as a platform for secretion of alpha-1-antitrypsin and other therapeutic proteins. The utility of this approach for treating AAT deficiency was tested in murine myocytes in vitro and in vivo. Serum concentrations were 100,000-fold higher than those previously observed with AAV vectors in muscle and at levels that would be therapeutic if achieved in humans. High-level expression was delayed for several weeks but was sustained for over 15 weeks. Immune responses were dependent upon the mouse strain and the vector dosage. These data suggested that recombinant AAV vector transduction of skeletal muscle could provide a means for replacing AAT or other essential serum proteins but that immune responses may be elicited under certain conditions.

Wilcke et al. (1999) examined attitudes about disclosing the identities of family members to a physician to ensure diffusion of genetic risk information within affected families, by means of a questionnaire study of Danish patients with alpha-1-antitrypsin deficiency (symbolized A1AD), their relatives, and a control group of Danish citizens. Only 2.8% objected to disclosing the identity of children, 9.1% objected to disclosing the identity of parents, and 6.7% objected to disclosing the identity of sibs. When genetic tests were offered to a sister, 75.4% of screened individuals with severe A1AD (phenotype 'piZ') and 66.8% of piZ probands thought that the physician should say who was ill. Important reasons for informing a sister at risk were, for 58%, the opportunity to prevent disease and, for 41% of piZ-probands, the opportunity to maintain openness in the family and to avoid uncertainty. The women were less prone to disclose the identity of sibs. Wilcke et al. (1999) concluded that the genetic counselor should ensure that relatives are properly informed about their risk of a severe genetic disorder, such as A1AD, in which disability can be prevented by change of lifestyle or by careful management. Because of a certain amount of ambivalence encountered in affected families, they recognized the necessity to exercise flexibility and responsiveness to individual circumstances when asking for relatives' identity and when approaching relatives.

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 is 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 of 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, and also provided a proof of principle for therapeutic use of autophagy enhancers.

Yusa et al. (2011) showed that a combination of zinc finger nucleases and piggyBac technology in human induced pluripotent stem cells (iPSCs) can achieve biallelic correction of a point mutation (glu342 to lys; 107400.0011) in the alpha-1-antitrypsin gene that is responsible for alpha-1-antitrypsin deficiency. Genetic correction of human iPSCs restored the structure and function of alpha-1-antitrypsin in subsequently derived liver cells in vitro and in vivo. Yusa et al. (2011) stated that this approach was significantly more efficient than any other gene-targeting technology then available and crucially prevented contamination of the host genome with residual nonhuman sequences. The authors concluded that their results provided the first proof of principle for the potential of combining human iPSCs with genetic correction to generate clinically relevant cells for autologous cell-based therapies.


Family studies indicated recessive inheritance of antitrypsin deficiency.

In early studies, heterozygotes, who can be detected chemically, were unaffected clinically; later studies suggested that heterozygosity may predispose to lung disease (Lieberman, 1969). For example, of 12 patients with obstructive lung disease present before age 40 years, 2 were judged by Tarkoff et al. (1968) to be homozygous for the deficiency and 1 heterozygous. Among 103 patients, Kueppers et al. (1969) found 5 homozygotes and 25 heterozygotes for the deficiency gene. They suggested that, especially in males, heterozygosity may predispose to chronic obstructive lung disease. Stevens et al. (1971) concluded that heterozygotes may develop emphysema qualitatively like that in homozygotes, but at a later age. The importance of prompt treatment of respiratory infections and avoidance of proteolytic aerosols, smoking and employment entailing exposure to respiratory irritants are important preventive measures in these families.

To study the question of the role of alpha-1-antitrypsin heterozygosity in the etiopathogenesis of chronic obstructive pulmonary disease (COPD) and to obviate the difficulties of precise diagnosis, Klasen et al. (1986) used a well-defined subgroup suffering from so-called 'flaccid lung.' In these persons, there is a loss of elasticity of the lung parenchyma with high compliance. Flaccid lung can be found with a high vital capacity, with spontaneous pneumothorax, in patients with giant bullae, and in all patients with lung emphysema. Klasen et al. (1986) found a relative risk of 12.5 for PI ZZ persons and 1.8 for MZ persons. They concluded that the risk of MZ persons compared to MM persons is almost negligible and that whether the MZ person develops lung disease is probably highly influenced by environmental and perhaps other genetic factors.

Dahl et al. (2002) reported on a study in Copenhagen to determine whether the MZ intermediate alpha-1-antitrypsin deficiency affects pulmonary function and disease. They randomly selected 9,187 adults from the Danish general population and followed them over a 21-year period; 451 (4.9%) carried the MZ genotype. Plasma antitrypsin levels were 31% lower in MZ heterozygotes than in persons with the MM genotype. They found that MZ heterozygotes had a slightly greater rate of decrease in FEV1 measure of pulmonary function and were modestly overrepresented among persons with airway obstruction and chronic obstructive pulmonary disease (COPD; 606963). They estimated that in the population at large, MZ heterozygosity may account for a fraction of COPD cases (on the order of 2%), similar to the percentage of persons with COPD who have the severe but rare ZZ genotype. Because the incidence of heterozygosity is so much higher than that of homozygosity, alpha-1-antitrypsin heterozygosity is as important a public health problem as homozygosity.

From study of 60-year-old twins with ZZ alpha-1-antitrypsin deficiency, one a heavy smoker who developed severe emphysema and the other a lifelong nonsmoker who was asymptomatic with only mild evidence of obstructive pulmonary disease, Kennedy and Brett (1985) demonstrated the importance of the environmental factor. A brother died at age 40 years of emphysema.

Population Genetics

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.

Alpha-1-antitrypsin deficiency is said to be rare among Japanese. 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.

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 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.

On the basis of data from previously published genetic epidemiologic studies, de Serres et al. (2003) estimated the frequency of AAT deficiency in France, Italy, Portugal, and Spain. In another report, de Serres et al. (2003) focused on the distribution of the PiS and PiZ deficiency alleles in Australia, Canada, New Zealand, and the United States.

Among 15,484 ethnically diverse individuals screened for alpha-1 antitrypsin deficiency carrier status, Lazarin et al. (2013) identified 1,178 carriers (7.6%), for an estimated carrier frequency of approximately 1 in 13. Forty-seven 'carrier couples' were identified. Thirty-eight individuals were identified as homozygotes or compound heterozygotes. Among 8,570 individuals of northern European origin, Lazarin et al. (2013) identified a carrier frequency of 1 in 10. Among 747 individuals of east Asian origin, the carrier frequency was 1 in 249.

Molecular Genetics

Deficiency of protease inhibitor activity is associated with several of the electrophoretic variants of serum alpha-1-antitrypsin; Axelsson and Laurell (1965) first suggested that the genes for electrophoretic variants are allelic with the deficiency 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).

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).

By means of isoelectric focusing, Weber and Weidinger (1988) found a PI variant that they called PI S (Cologne). A father and daughter were heterozygous. Alpha-1-antitrypsin concentrations were within the normal range.

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.

Bamforth and Kalsheker (1988) discussed a rare Pi null allele that in homozygous state leads to pulmonary emphysema at an early age. In 3 families, all the affected individuals presented in early childhood with recurrent chest infections and wheezing, presumably related to passive smoking. Even though there was no detectable AAT, no partial or complete deletion of the gene could be identified.

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 (M358R; 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 and results in a bleeding disorder (Lewis et al., 1978; Owen et al., 1983).

SERPINA1 Haplotypes Associated with Chronic Obstructive Pulmonary Disease

The most widely recognized candidate gene in COPD (see 606963) 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.


Crystal (1990) gave a comprehensive review of the pathogenetic relationship between AAT deficiency and emphysema and liver disease, including a detailed listing of the various mutations that have been identified and a discussion of the possibilities for therapy.

Animal Model

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 Siiyama 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.


Eriksson (1989) gave an interesting historical account including the pedigree of his first family (Eriksson, 1965).

Several reports (Bell and Carroll, 1973; Kuhlenschmidt et al., 1974; Eriksson and Larsson, 1975) had suggested that the defect may be in a sialyltransferase and that deficiency of antitrypsin in the blood is the result of impaired secretion from hepatocytes, increased clearance of the undersialated protein, or both. It is difficult to see how this could cause codominant inheritance or account for the different types that appear to be the products of at least 30 different alleles, unless an amino acid substitution interferes with sialidation.