Italian researchers have associated a newly identified genetic variant of the gene SERPINA1 with bronchiectasis. Their study, “A New SERPINA-1 Missense Mutation Associated with Alpha-1 Antitrypsin Deficiency and Bronchiectasis,” appeared in the journal Lung.
SERPINA1 encodes a protein called alpha-1-antitrypsin (AAT) which is produced by the liver and is a key inhibitor of protein degradation. So far, more than 100 genetic alterations have been identified in the SERPINA1 gene, which can reduce production of AAT.
AAT deficiency is a rare condition that can lead to destruction of lung air passage structures, a process known as panacinar emphysema. Bronchiectasis, with or without emphysema, has been described in AAT deficiency among other manifestations. This deficiency can also cause liver disease and skin disorders.
Because of the rarity of this condition, little it is known about it. This makes harder for physicians to identify the presence of SERPINA1 gene disease-causing mutations or recognize their impact in a clinical setting.
Investigators at Italy’s University of Foggia have for the first time identified a genetic variant of SERPINA1 gene as being a potential cause of bronchiectasis.
Upon analyzing the genetic sequence of the SERPINA1 gene in a 52-year-old woman diagnosed with bronchiectasis and presenting pulmonary exacerbations, the research team found the Ile74Asn genetic mutation. This led to a change of an amino acid in the sequence of the AAT protein, which was predicted to alter the protein’s structure and consequently its function.
“This mutation lies in an important region of the gene, and the prediction analysis suggests it would be highly damaging to protein structure and function,” researchers wrote. “This mutation has never been previously identified, and it is interesting to note the association with bronchiectasis in the absence of emphysema.”
A detailed clinical evaluation allowed the team to rule out other potential causes for the pulmonary exacerbations, such as presence of cystic fibrosis, bacterial infections or fungal infections.
Assessment of AAT levels in the blood showed that the patient had lower levels of AAT than normal. This result confirmed the potential negative effect of the genetic variant detected.
“The identification of new variants is certainly helpful in order to identify critical regions in the SERPINA1 more prone to deleterious effects as well as their contribution to the burden of AATD [AAT deficiency],” the team wrote.
Given these results and previous reports, the investigators speculated that this newly genetic mutation may reduce AAT protein levels and activity, causing a metabolic imbalance in lung tissues and promoting their destruction. This ultimately leads to bronchiectasis. However, further studies are needed to confirm this hypothesis.