Alpha1Center

AAT Deficiency
The synthesis of AAT is controlled by a pair of genes at the proteinase inhibitor (Pi) locus. The genes are inherited as co-dominant alleles (products of both genes can be found in the circulation). Many abnormal variants have been very well characterized; they result from point mutations in the gene, and most commonly have one or two amino acid substitutions when compared to the normal protein. Some of these changes result in little (or rarely, no) AAT in the circulation.
Heterozygotes and individuals with the S variant usually do not have "normal" circulating levels of AAT. However, in this discussion the term "AAT deficiency" will be reserved for individuals with severely diminished AAT levels (<11 M).

Variant types of AAT: More than 75 different genetic variants of AAT are now recognized, but many of these are quite rare. AAT in the serum can be characterized by phenotyping, which is accomplished by isoelectric focusing of serum. DNA for AAT (most often in white blood cells) can also by typed by genotyping, which is accomplished by allele-specific amplification. The most common variants of AAT will be discussed below. The remainder are beyond the scope of this review, but most are described in the excellent review by Brantly.

Genetic transmission: Individuals with AAT deficiency have two deficient alleles for the protein. Thus, the deficiency is an inherited as an autosomal recessive condition. Brothers and sisters of deficient individuals have a 25% chance of also having the condition. Children of deficient individuals can be expected to be heterozygotes ("carriers") for the deficiency. These children have only a small risk of being AAT deficient, and this risk is present only if the partner of the deficient individual is a carrier. Phenotyping or genotyping are necessary to reliably detect carriers, since AAT levels of normals and carriers overlap to some extent.

The normal M alleles: The normal M alleles represent by far the largest group of AAT alleles. They result in normal amounts, and normal functionality, of AAT in the blood. The M1, M2, and M3 alleles differ only subtly from one another, and the differences are not clinically important.

The Z variant: By far the most prevalent type of clinically important AAT deficiency is classified as phenotype Pi Z. In these individuals, isoelectric focusing reveals only an abnormally migrating Pi Z type AAT. These individuals may be either Pi ZZ homozygotes or Pi Znull heterozygotes, since no AAT attributable to the null genes can be found in the circulation. Genotyping is necessary to distinguish between these two possibilities, although family studies of the pattern of inheritance of low AAT levels may be helpful.

The Z variant has two amino acid substitutions when compared to the most prevalent normal type of AAT. It is subtly abnormal as an inhibitor of leukocyte elastase. However, the most striking abnormality in affected individuals is that circulating levels of the protein are only 10-15% of normal. When livers of these individuals are examined, the hepatocytes contain an abnormal accumulation of AAT.. The Pi Z type of AAT is secreted abnormally slowly by both hepatocytes and monocytes. This abnormality is thought to cause the deficiency. The exact cause of the abnormal secretion of Pi Z type AAT is a matter of current investigation. One of the amino acid substitutions (Glu342 Lys342) may result in misfolding of the AAT, leading to intracellular accumulation and intracellular degradation of the abnormal protein. The structural alteration in the Z variant appears to allow "loop-sheet polymerization" of the molecule, during which the reactive center loops of one molecule become inserted into an opening in the A sheet of another molecule.

The S variant: The S variant has a single amino acid substitution (Glu264 Val264) when compared with the most prevalent normal type of AAT. The S mutation is not associated with intracellular accumulation of the protein, and the S protein inhibits elastase normally. The amounts of the S protein that reach the circulation are slightly lower than normal, because of intracellular degradation of the AAT before it is secreted. The S allele is slightly more prevalent than the Z allele among U.S. Caucasians, and it is much more prevalent in the Iberian peninsula and neighboring countries. Individuals with the Pi S phenotype do not appear to be at increased risk for lung or liver disease.

Common heterozygotes: Pi MS individuals have one normal allele and one S allele. They have nearly normal, and occasionally normal, levels of AAT. They do not appear to be at increased risk for lung or liver disease.

Pi MZ individuals have one normal allele and one allele for the Z variant. They usually have decreased levels of AAT in their circulation; however, since they are capable of mounting an acute phase response, their levels can fall within the normal range (particularly if they are ill or are taking oral contraceptives). The livers of Pi MZ heterozygotes show mild intracellular accumulation of the protein. There appears to be minimal excess risk of lung or liver disease in Pi MZ heterozygotes, although studies have not consistently shown that there is no increased risk. For more information, see the excellent review by Hutchison. It seems to be advisable to offer a great deal of reassurance to Pi MZ heterozygotes regarding their own risk of developing lung or liver disease, but to counsel them about the risk of genetic transmission of the deficient allele.

Pi SZ individuals have one allele for the S variant and one for the Z variant (the classical deficiency variant). They have AAT levels that range from approximately 1/3 to 1/2 of normal. Pi SZ heterozygotes are more common than Pi Z (AAT deficient) individuals in American populations. The livers of Pi SZ heterozygotes show mild accumulation of AAT. Studies of the risk of disease in Pi SZ heterozygotes have reached variable conclusions; this issue is discussed in Hutchison's review. Based upon the studies published to date, it seems most appropriate to state that these individuals have little, and probably no, increased risk of clinically significant lung or liver disease. It again seems advisable to offer these individuals reassurance regarding their own risk, but to counsel them regarding the risk of transmission of the Z allele.