Identification and characterisation of seven novel SERPINA1 null mutations

Background- Alpha-1 antitrypsin (AAT) is a serine protease inhibitor, encoded by the highly polymorphic SERPINA1 gene. Mutations in this gene can lead to AAT deficiency (AATD) which is associated with a substantially increased risk of lung and liver disease. A group of rare mutations causing AATD, termed Null, are characterised by a complete absence of AAT in the plasma, that confer a particularly high risk of emphysema. Objectives- Here we reported the novel Null AAT mutations that we discovered during the Italian and Irish targeted detection programs of AATD. Methods-We 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.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 of the SERPINA1 gene. Results-We identified seven previously unidentified SERPINA1 Null mutations. Three are nonsense mutations, the others are frameshift mutations caused by deletion of one or two nucleotides. We also performed familial screening. Analysis of the clinical characteristics revealed the recurrence of lung symptoms and lung diseases in M/Null subjects, over 45 years-old, irrespective of their smoking habit. Conclusions We added seven more mutations to the list of SERPINA1 Null alleles. Moreover, we underlined 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.