Identification of a novel alpha1-antitrypsin variant

Abstract

Alpha-1-antitrypsin deficiency (A1ATD) is a genetic condition caused by SERPINA1 mutations, which results into decreased protease inhibitor activity in the serum and predisposes to emphysema and/or to liver disease due to accumulation of the abnormal protein in the hepatic cells. In most cases the clinical manifestations of A1ATD are associated with PIZZ (p.Glu366Lys; p.Glu366Lys (p.Glu342Lys; p.Glu342Lys)) or PISZ (p.Glu288Val; p.Glu366Lys (p.Glu264Val; p.Glu342Lys)) genotype, less frequently, deficient or null alleles may be present in compound heterozygous or homozygous A1AT deficient patients.We report the identification of a novel alpha1-antitrypsin variant in a 64-year old woman presenting with dyspnea on exertion. Imaging revealed bilateral bronchiectasis associated with moderate panacinar emphysema. The pulmonary function tests (PFTs) were subnormal but hypoxemia was noticed and A1AT quantitative analysis revealed a severe deficiency. DNA sequencing showed compound heterozygosity for the PIZ variant and a novel missense variant p.Phe232Leu (p.Phe208Leu). No specific treatment was proposed since PFTs were within the normal range at this stage of the disease. Close follow-up of pulmonary and hepatic parameters was recommended.

Clinical presentations of four patients with rare Alpha 1 Antitrypsin variants identified in a single US center

“…Although detecting rare/novel mutations can be challenging, recent sequencing techniques (NGS) should be employed when standard PCR and IEF tests suggest a normal genotype in patients with low/normal AAT levels. Gene sequencing techniques are able to detect rare/novel genotypes, and in some cases, can help to determine the most suitable course of treatment for patients with AATD [ 3 ]. Nevertheless, it should be noted that sequencing techniques are generally expensive to run and less widely available in general laboratory/clinic settings than more basic tests.…”

“…The primary function of AAT is to regulate serine proteases and protect the lungs from elastolytic damage by inhibiting the proteolytic enzyme neutrophil elastase [ 2 ]. Sequence variants of the SERPINA1 gene can result in low serum levels of AAT or subtle structural changes to the protein that reduce its functionality [ 3 ]. This deficit in functional AAT results in Alpha 1 Antitrypsin Deficiency (AATD), a condition associated with lung tissue destruction, emphysema and liver disease [ 4 ].…”

Serpin Family A Member 1 Is Prognostic and Involved in Immunological Regulation in Human Cancers

“…Serpin family A member 1 (SERPINA1) is located on chromosome 14 (14q32.1), encoding the protein Alpha1-antitrypsin (A1AT) that is a highly conserved protein and the dominant protease inhibitor, the inhibition capacity of which accounts for more than 90% of all plasma proteases [4]. SERPINA1 is expressed mainly in hepatocytes but is also synthesized in mononuclear phagocytes, neutrophils, and intestinal epithelial cells [5]. SERPINA1 plays a crucial role in the maintenance of cell homeostasis through irreversibly inhibiting a variety of serine endopeptidases.…”