Analysis of the Alpha-1-Antitrypsin Deficient Alleles M3S, MZ, and ZZ by Biochemical and Molecular Methods: A Family Study

Abstract

Deficiency of alpha-1-antitrypsin (alpha(1)-AT, a major protease inhibitor controlling tissue degradation) is a genetic disorder transmitted in a codominant autosomal form. It has more than 100 genetically determined variants. This study attempted to determine the degree of association between serum alpha(1)-AT levels and phenotypes and to provide a strategy for reliable laboratory evaluation of deficiencies. The study group consisted of a 38-year-old male proband with clinical features of emphysema, his first-degree relatives, and healthy controls. Family history revealed a four-generation pedigree. Genomic DNA was isolated from peripheral blood leukocytes. Alpha-1-AT levels were determined from human serum by immunonephelometry. Phenotypes were determined by isoelectric focusing of blood samples. DNA sequences of coding exons were analyzed by the amplification DNA technique and direct sequencing. Inheritance and plasma levels of the ZZ, MM, M3S, and MZ phenotypes were confirmed by the family study. In the family members with deficiencies, plasma concentrations were 22.55% +/- 5.15 (ZZ), 84.18% +/- 5.18 (M3S), and 61.06% +/- 7.15 (MZ) of the normal MM level. We found a close association between alpha(1)-AT level and genotype. A combination of genotyping, quantification, and phenotyping is the optimal strategy for the laboratory evaluation of alpha(1)-AT deficiency.

Monogenic gene variants in lung transplant recipients with usual interstitial pneumonia

“…The variants for SERPINA1 in this study were heterozygous and are not able to cause disease without a second disease-causing variant in the same gene. The p.(Glu366Lys) variant removes a salt bridge to Lys290 and a hydrogen bond to Thr203, causing misfolding of the protein within the endoplasmic reticulum, which results in a lack of secretion from hepatocytes and a reduction of plasma α-1-antitrypsin levels to 10–15% of normal in homozygotes [ 28 ] and to 61–77% in heterozygotes [ 29 , 30 ]. Heterozygous carrier of p.(Glu366Lys) may have moderately decreased to normal serum α-1 antitrypsin levels and could therefore influence pulmonary phenotype.…”