Practical genetics: alpha-1-antitrypsin deficiency and the serpinopathies

Abstract

Alpha-1-antitrypsin (a 1 -antitrypsin) is the archetypal member of the serine proteinase inhibitor or serpin superfamily. The most common severe deficiency variant is the Z allele, which results in the accumulation of mutant protein within hepatocytes. This 'protein overload' causes neonatal hepatitis, cirrhosis and hepatocellular carcinoma. The lack of circulating plasma a 1 -antitrypsin results in early-onset panlobular emphysema. The mechanism underlying the deficiency of Z a 1 -antitrypsin is due to an aberrant conformational transition within the protein and the formation of chains of polymers that tangle within the secretory pathway of hepatocytes. This mechanism also underlies the plasma deficiency of other members of the serpin superfamily to cause a class of diseases called the serpinopathies. Specifically mutant alleles of antithrombin, C1-inhibitor and a 1 -antichymotrypsin have been reported that favour the spontaneous formation of polymers and the retention of protein within hepatocytes. The consequent lack of plasma antithrombin, C1-inhibitor and a 1 -antichymotrypsin results in thrombosis, angio-oedema and emphysema, respectively. Moreover, the polymerisation of mutants of neuroserpin results in the retention of polymers within neurones to cause the inclusion body dementia, familial encephalopathy with neuroserpin inclusion bodies or FENIB. We review here the genetic and molecular basis and clinical features of a 1 -antitrypsin deficiency, and show how this provides a platform to understand the other serpinopathies. Keywords: a 1 -antitrypsin; a 1 -antichymotrypsin; antithrombin; C1-inhibitor; neuroserpin; serpins; serpinopathies Alpha-1-antitrypsinGene structure and common mutations Alpha-1-antitrypsin (a 1 -antitrypsin) is a 394 amino acid, 52 kDa, acute-phase glycoprotein synthesised by the liver and macrophages and present in the plasma at a concentration of 1.5 -3.5 g/l. It functions as an inhibitor of a range of proteolytic enzymes, but its primary role is to inhibit the enzyme neutrophil elastase. a 1 -Antitrypsin is subject to genetic variation resulting from mutations in the 12.2 kb, 7-exon gene at q31 -31.2 on chromosome 14.1 Over 75 allelic variants have been reported and classified using the protease inhibitor (PI) nomenclature that assesses a 1 -antitrypsin mobility in isoelectric focusing analysis. 2Normal a 1 -antitrypsin migrates in the middle (M) and variants are designated A -L if they migrate faster than M, and N -Z if they migrate more slowly. The most clinically relevant variants are the S (Glu264Val) and Z (Glu342Lys) alleles and the uncommon Null alleles that result from point mutations that introduce premature stop codons.

Alpha-1-Antitrypsin Deficiency in Children: Case Series

“…Время на синтез молекулы А1АТ занимает порядка 1,5 ч, что позволяет относить А1АТ к быстросе-кретируемым белкам [2]. Период полураспада составляет от 3 до 6 сут [17]. Сывороточная концентрация А1АТ составляет 1,2-2,4 г/л (по данным нефелометрии -от 2 до 4 г/л) и может различаться у одного и того же человека в зависимости от сопутствующих заболеваний и проводимой терапии (так, при приеме эстрогенов уровень А1АТ повышается) [17].…”

“…Период полураспада составляет от 3 до 6 сут [17]. Сывороточная концентрация А1АТ составляет 1,2-2,4 г/л (по данным нефелометрии -от 2 до 4 г/л) и может различаться у одного и того же человека в зависимости от сопутствующих заболеваний и проводимой терапии (так, при приеме эстрогенов уровень А1АТ повышается) [17]. В норме печень еже-суточно секретирует 34 мг/кг массы тела А1АТ, а при развитии воспалительного и опухолевого процесса кон-центрация А1АТ увеличивается в 2-5 раз вследствие воспаления [18].…”

“…Ген обладает высокой полиморфностью: в настоящее время известно более 500 аллельных вариантов, кли-ническое значение из них имеют около 30 [17]. В зави-симости от вырабатываемого продукта аллели А1АТ подразделяются на четыре класса: нормальные -I, дефицитные -II, нулевые -III, с нарушением функ-ции -IV [19].…”

Genetics of ?1 Anti-Trypsin (AAT) Deficiency

“…Traditionally, each variant is identified by its speed of migration on polyacrylamide gel electrophoresis called isoelectric focusing (IEF) in a pH 4-5, the most common forms being F (fast), M (medium), S (slow) and Z (very slow). Alteration in the speed of movement through a gel occurs because of variation in protein charge, due to the changes in amino acid composition [10].…”

Alpha One Antitrypsin Deficiency: A Pulmonary Genetic Disorder

“…A1AT is an acute phase reactant with a normal concentration in serum of 20-53 micromole/L. Alpha one antitrypsin is a member of the serpin family of protease inhibitors, which regulate important proteolytic enzyme cascades including the coagulation cascade, complement cascade, and plasmin inhibition (Crowther et al, 2004). Serpins not only inhibit proteases but cause a conformational change in their structure readying them for destruction.…”