New -Acting Variants in PI*S Background Produce Null Phenotypes Causing Alpha-1 Antitrypsin Deficiency.

Alpha-1 antitrypsin deficiency (AATD) is an inherited condition characterized by reduced levels of serum AAT due to mutations in the (Serpin family A member 1) gene. The PiS (Glu264Val) is one of the most frequent deficient alleles of AATD, showing high incidence in the Iberian Peninsula. Herein, we describe two new alleles carrying an S mutation but producing a null phenotype: QO and QO. The new alleles were identified by sequencing the gene in three patients who had lower AAT serum levels than expected for the initial genotype. These alleles are the result of combined mutations in a PIS allele. Sequencing detected the S mutation with Tyr138Cys (S+Tyr138Cys) in two patients, whereas a third one had the S mutation with Pro391Thr variant (S+Pro391Thr). When expressed in a cellular model, these variants caused strong AAT polymerization and very low AAT secretion to almost undetectable levels. The isoelectric focusing method for plasma AAT phenotyping did not show AAT protein encoded by the novel mutant alleles, behaving as null. We called these alleles PIS-plus because the S variant was phased with another variant conferring more aggressive characteristics to the allele. The current data demonstrate that the clinical variability observed in AATD can be explained by additional genetic variation, such as dual -acting variants in the gene. The possible existence of other unrevealed variants combined in the PIS alleles should be considered to improve the genetic diagnosis of the patients.