Alpha-1-antitrypsin deficiency: Genetic variations, clinical manifestations and therapeutic interventions

Alpha‐1 antitrypsin deficiency panniculitis: clinical and pathologic characteristics of 10 cases

“…AATD is an autosomal co‐dominant genetic condition characterized by decreased concentration and activity of alpha‐1 antitrypsin (AAT) in blood and body tissues. AAT is an acute‐phase glycoprotein that inhibits neutrophil proteases like elastase . Severe AAT predisposes to early‐onset emphysema, chronic obstructive pulmonary disease, liver disease, and much less frequently systemic vasculitis and neutrophilic panniculitis .…”

“…The normal, wild type, is PiM and is characterized by normal functional activity of AAT. Deficient alleles are associated with decreased plasma levels of AAT, the most common of which is the Z allele . Null alleles lead to no detectable AAT protein and are denoted Q0 rather than Pi.…”

“…Dysfunctional variants lead to normal levels, but dysfunctional AAT. Worldwide, AATD affects approximately one in 2500 individuals . Diagnosis of AATD is made by first measuring the serum levels of AAT.…”

Engineering the serpin α1‐antitrypsin: A diversity of goals and techniques

“…In individuals with α 1 ‐AT deficiency, an autosomal co‐dominant disease, circulating levels of α 1 ‐AT are as low as 10% of normal, contributing to a high risk for chronic obstructive pulmonary disorder (COPD)/emphysema and cirrhosis of the liver . α 1 ‐AT deficiency has been linked to over 30 pathogenic variants, with the E264V “S” and E342K “Z” variants accounting for most cases due to a particularly high frequency among people of European decent …”

“…Such demands include: metastability; optimal RCL for cognate proteinase recognition; correct length of the RCL for rapid loop insertion; compatibility of RCL residues for integration into β‐sheet A, with the burial of alternate side chains into the hydrophobic interior; and stability of the ensuing complex. There are numerous ways in which a serpin can be inactivated by mutation, either by nature (reviewed in References ) or in the course of nonproductive protein engineering efforts. Such engineering efforts can be refined by taking advantage of the large literature of loss‐of‐function mutations generated during structure and function studies, such as those involving the proximal and distal regions of the RCL, changes near the “shutter” region where two strands of β‐sheet A must open to allow RCL insertion, RCL length, and extensive loop exchange variants in which all or much of the RCL of one serpin has been substituted for the native RCL of another .…”