Abstract
BackgroundAlpha-1 antitrypsin (AAT) is the most abundant circulating antiprotease and is a member of the serine protease inhibitor (SERPIN) superfamily. The gene encoding AAT is the highly polymorphic SERPINA1 gene, found at 14q32.1. Mutations in the SERPINA1 gene can lead to AAT deficiency (AATD) which is associated with a substantially increased risk of lung and liver disease. The most common pathogenic AAT variant is Z (Glu342Lys) which causes AAT to misfold and polymerise within hepatocytes and other AAT-producing cells. A group of rare mutations causing AATD, termed Null or Q0, are characterised by a complete absence of AAT in the plasma. While ultra rare, these mutations confer a particularly high risk of emphysema.MethodsWe performed the determination of AAT serum levels by a rate immune nephelometric method or by immune turbidimetry. The phenotype was determined by isoelectric focusing analysis on agarose gel with specific immunological detection. DNA was isolated from whole peripheral blood or dried blood spot (DBS) samples using a commercial extraction kit. The new mutations were identified by sequencing all coding exons (II-V) of the SERPINA1 gene.ResultsWe have found eight previously unidentified SERPINA1 Null mutations, named: Q0cork, Q0perugia, Q0brescia, Q0torino, Q0cosenza, Q0pordenone, Q0lampedusa, and Q0dublin . Analysis of clinical characteristics revealed evidence of the recurrence of lung symptoms (dyspnoea, cough) and lung diseases (emphysema, asthma, chronic bronchitis) in M/Null subjects, over 45 years-old, irrespective of smoking.ConclusionsWe have added eight more mutations to the list of SERPINA1 Null alleles. This study underlines that the laboratory diagnosis of AATD is not just a matter of degree, because the precise determination of the deficiency and Null alleles carried by an AATD individual may help to evaluate the risk for the lung disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-014-0172-y) contains supplementary material, which is available to authorized users.
Highlights
Alpha-1 antitrypsin (AAT) is the most abundant circulating antiprotease and is a member of the serine protease inhibitor (SERPIN) superfamily
Alpha-1 antitrypsin deficiency (AATD) (MIM # 613490) is an inherited condition caused by mutations within the polymorphic SERPINA1 gene and is characterised by decreased serum AAT concentrations
Over 100 mutations leading to AAT deficiency have been identified to date and are associated with varying degrees of risk for lung and liver disease
Summary
Alpha-1 antitrypsin (AAT) is the most abundant circulating antiprotease and is a member of the serine protease inhibitor (SERPIN) superfamily. Mutations in the SERPINA1 gene can lead to AAT deficiency (AATD) which is associated with a substantially increased risk of lung and liver disease. Alpha-1 antitrypsin deficiency (AATD) (MIM # 613490) is an inherited condition caused by mutations within the polymorphic SERPINA1 gene and is characterised by decreased serum AAT concentrations. The majority of individuals diagnosed with severe AATD are homozygous for the Z mutation, and have circulating AAT levels reduced to 10-15% of normal. This is because the Z mutation prompts the AAT protein to polymerise and accumulate within the endoplasmic reticulum of hepatocytes, causing impaired secretion [10]. If the slowly polymerising S variant of AAT is inherited with a rapidly polymerising variant such as Z, the two variants when co-expressed can interact to form heteropolymers, leading to cirrhosis and plasma deficiency [13]
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