Aat Deficiency And Disease

Homozygous Z individuals are predisposed to developing childhood cirrhosis[7] and pulmonary emphysema in early

Aat Deficiency
Fig. 1 Interaction of the protease trypsin with AAT. Trypsin docks on to the exposed RCL, cleaves the RCL, and the loop inserts into a sheet. The protease is then translocated to the opposite pole of the molecule and the active site of the protease is distorted. (See Ref. [1].)

adult life, particularly in cigarette smokers.[8] The Z variant is prevalent in northern Europeans, with a frequency of about 1.5% in Sweden and Norway, and greater than 2% in Denmark, Latvia, and Estonia.[9] It is extremely rare in Asian and African populations. The Z protein is synthesized normally, but tends to polymerize in hepatocytes. The polymerization results from an intermolecular interaction in which one RCL inserts into a space in the A-sheet. The Z mutation favors polymerization and the accumulated aggregates cause damage to the hepatocytes, which can result in childhood cirrhosis.[10] Only about 3% of PI Z individuals develop severe liver disease that often requires liver transplantation—the only effective treatment for them.[11] In a prospective screening study carried out in 200,000 newborns in Sweden, 120 children with PI ZZ were followed up.[12] Eighteen percent of the PI Z children developed clinically recognizable liver abnormalities, 7.3% had prolonged obstructive jaundice with marked evidence of liver disease, 4.1% had prolonged jaundice with mild liver disease, and 6.4% had other abnormalities suggestive of liver disease such as hepatomegaly, splenomegaly, or unexplained failure to thrive. The most common presentation is the ''neonatal hepatitis syndrome,'' which is characterized by conjugated hyperbilirubinemia and raised serum transminases. Features of cholestasis generally appear between 4 days and 2 months of age, and can persist for up to 8 months. About 14-29% of individuals with neonatal hepatitis syndrome have been found to have AAT deficiency. Most of these cases resolve without apparent long-term consequences.

The association with pulmonary emphysema is related to cigarette smoking, highlighting an important interaction between genetic and environmental factors. This is thought to arise from the action of neutrophil elastase, a major protease of neutrophils released during an inflammatory state. Deficiency of AAT, its major inhibitor,

Fig. 2 AAT PI types separated according to their isoelectric point. A pH gradient of 4-5 is used and the variants migrate as two major bands, designated 4 and 6, and minor bands 2, 7, and 8. Variation in migration results from amino acid substitutions. The Z variant migrates toward the cathode and the S variant has an intermediate position to M and Z.

Fig. 2 AAT PI types separated according to their isoelectric point. A pH gradient of 4-5 is used and the variants migrate as two major bands, designated 4 and 6, and minor bands 2, 7, and 8. Variation in migration results from amino acid substitutions. The Z variant migrates toward the cathode and the S variant has an intermediate position to M and Z.

Table 1 Normal and deficiency variants of AAT

Allele

Base allele

Exon

Mutation

Normal AAT alleles

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