Molecular characterization of PI*Q0_{la palma}, a new alpha‐1‐antitrypsin null allele that combines two defective genetic variants

Known Mutations at the Cause of Alpha-1 Antitrypsin Deficiency an Updated Overview of SERPINA1 Variation Spectrum

“…The five variants M Malton , M Palermo , M Nichinan, Q0 LaPalma and S Iiyama are connected by their alterations of the contiguous 51-53 residues, where the Phe-Phe-Ser sequence is fundamental to maintain a stable conformation of the shutter domain (Figure 3; Table 1). [67][68][69][70][71][72] The deletion of a phenylalanine p.Phe52del (rs775982338) found in M Malton , M Palermo or M Nichinan and the replacement of serine by a phenylalanine p.Ser53Phe (rs55819880) as observed in S Iiyama , cause in a similar way to the Z allele the opening of the breach/shutter, enhancing the susceptibility of these variants to polymerize. However, whereas the S Iiyama allele is an extremely rare variant identified in a few families from Japan, 67,68,73 the other alleles characterized by the p.Phe52del are widely distributed across different human groups as indicated by the genomics studies of large control populations, where this mutation was found at low or very frequencies (<0.01-0.04%) ( Table 1).…”

“…No evidence of hepatic dysfunction was detected in Q0 LaPalma carriers. 72 Whereas M Malton and M Palermo alleles have been identified in several AATD cases across different European and North African countries, 13,74,75 the M Nichinan was only reported in AATD subjects from Japan. 73 So far, only a few studies performed a clinical evaluation of M Malton carriers, homozygous and heterozygous, confirming the association of p.Phe52del with both pulmonary and hepatic diseases.…”

“…Continued). The list of known alleles was retrieved from AATD specialized literature 3,13,[70][71][72][82][83][84][85]89,90,92,94,99,[104][105][106][107][108][109][110][111]. Molecular background is provided to discriminate alleles carrying the same mutation.…”