Identification and characterisation of twenty-two novel SERPINA1 pathological mutations

Abstract

Background: Alpha-1 antitrypsin (AAT) is a serine protease inhibitor, encoded by the highly polymorphic SERPINA1 gene. Mutations in the SERPINA1 gene can lead to AAT deficiency (AATD), which is associated with a substantially increased risk of lung and liver disease.

Objectives: Here we reported 22 novel AAT pathological mutations that we discovered during the Italian and Irish targeted detection programs of AATD during the last years.

Methods: We performed the determination of AAT serum levels by a rate immune nephelometric method. The phenotype was determined by isoelectric focusing analysis. DNA was isolated from whole peripheral blood, dried blood spot (DBS) samples or buccal swabs using a commercial extraction kit. The new mutations were identified by sequencing exonic and part of the intronic portions of the SERPINA1 gene by Sanger methods or Next Generation Sequencing. Predictive algorithm have been applied to them.

Results: We found 22 previously unidentified SERPINA1 pathological mutations. Three of them are Null mutations, the others are non-synonymous mutations causing protein deficiency. According to clinical data, the protein structural context and residue conservation, the variants have been classified as “pathogenic”, “likely pathogenic” and “likely benign”.

Conclusions: We added twenty-two more mutations to the list of SERPINA1 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.