Researchers identified novel alleles of SERPINA1, the gene that encodes alpha-1 antitrypsin (AAT), through an AAT deficiency (AATD) screening program. The study was published in Chronic Obstructive Pulmonary Diseases.

“Our laboratory has been screening individuals for AAT variants for several years using a series of improving and more efficient technologies to simplify the accurate identification of new alleles,” the researchers said.

In this study, the researchers identified 22 novel SERPINA1 alleles from the Alpha-1 Foundation DNA and Tissue Bank at the University of Florida in Gainesville. Most were discovered in asymptomatic individuals who underwent genetic testing due to a family history of AATD. The analysis included more than 500,000 individuals.


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Most alleles were either null (n=13) or deficient (n=7), with the majority of novel null alleles resulting from single-base deletions and subsequent sequence frameshifts and premature termination codons. Moreover, the researchers identified 2 normal alleles, Pconnellsville and Nhartford city.

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Three novel mutations were identified in individuals presenting with pulmonary symptoms at a younger age:

  • Iorange was identified in a 33-year-old woman with a history of asthma and a family history of chronic obstructive pulmonary disease. She carried a Z allele, as well as a heterozygous mutation at codon 39 (Arg CGC > Cys TGC) on an M2 (Arg101 CGT > His CAT) background.
  • QOsan francisco was identified in a 41-year-old woman with a history of hepatitis, asthma, and emphysema who was receiving supplemental oxygen and AAT augmentation therapy. She was homozygous for a null allele in exon II (Pro28 CCC, insertion of T, shift to stop TGA 32). Her 2 children were also tested, and they were both heterozygous for this novel allele.
  • QOknoxville was identified in a 57-year-old man with a family history of several lung diseases. He had a Z allele and a novel null allele (a frameshift deletion in exon V resulting in a stop codon at 373). His son, who had asthma, was also heterozygous for this null allele, and an asymptomatic niece was found to have the SQOknoxville genotype.

Rare deficiency alleles have limited pathological relevance for most individuals with AATD. However, they might be important for the development of novel therapies to manage the consequences of misfolded AAT.

Reference

Wiesemann GS, Oshins RA, Flagg TO, Brantly ML. Novel SERPINA1 alleles identified through a large alpha-1 antitrypsin deficiency screening program and review of known variants. Chronic Obstr Pulm Dis. Published online October 24, 2022. doi:10.15326/jcopdf.2022.0321