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Molecular characterization of PI *Q0 la palma , a new alpha‐1‐antitrypsin null allele that combines two defective genetic variants
Author(s) -
HernándezPérez J.M.,
RamosDíaz R.,
FumeroGarcía S.,
Pérez J.A.
Publication year - 2017
Publication title -
clinical genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.543
H-Index - 102
eISSN - 1399-0004
pISSN - 0009-9163
DOI - 10.1111/cge.12889
Subject(s) - allele , alpha (finance) , genetics , biology , pi , microbiology and biotechnology , null allele , gene , biochemistry , medicine , construct validity , nursing , patient satisfaction
To the Editor: Alpha-1-antitrypsin (α1AT) encoded by the SERPINA1 gene is the most abundant protease inhibitor (PI) in human serum (1). The α1AT deficiency (α1ATD) is an autosomal hereditary trait (OMIM #613490) characterized by decreased levels and/or function of circulating α1AT, which predisposes to develop pulmonary emphysema and less frequently liver disease. The SERPINA1 deficiency alleles more commonly found in Caucasians populations are PI*S and PI*Z (1). As a result of targeted-detection programs or case-findings, more than 50 rare deficient alleles have been discovered (2), including a heterogeneous subgroup of null alleles in which diverse molecular mechanisms underlie total absence of circulating α1AT (3). These null alleles are of particular interest because they are associated with an earlier onset and greater severity of pulmonary emphysema (4) but never with liver disease (1). Herein, we describe a new SERPINA1 null allele that was identified in 37-year-old woman, heavy smoker, with severe airway obstruction (FEV1 48% of predicted) and diffuse panacinar emphysema, which made us to consider diagnosis of α1ATD. The mean concentration of α1AT in the patient’s serum was 8.5 mg/dl, far below the protective level of 50 mg/dl (1), and phenotyping by isoelectric focusing (IEF) only detected the PiZ type of α1AT (Fig. 1a). The extremely low level of serum α1AT and the very early manifestation of emphysema led us to perform a genetic study of the patient. After informed consent and under the approval of the ethics committee of the Hospital General de La Palma (Canary Islands, Spain), samples were taken from this patient and eight members of her family. Analysis of the SERPINA1 gene with FRET probes revealed the presence of non-S/S (rs17580) and non-Z/Z (rs28929474) variants in the index case. This discrepancy between genotype (presumably PI*SZ) and phenotype (PiZ) suggested us that the SERPINA1 allele bearing the S variant could be affected by other sequence alterations that prevent the production of circulating α1AT. This allele was selectively amplified and sequenced. This haplotype analysis (Fig. 1b) revealed that the S variant was in cis configuration with the ΔPhe52 variant (rs863225263) within a M1-Val213 sequence (GenBank NG_008290.1). The S and ΔPhe52 variants, when present separately in a Fig. 1. Characterization of PI*Q0la palma allele. (a) α1AT phenotyping of patient by IEF. Genotypes of reference samples are indicated above lanes. M, normal allele. (b) Sequencing electropherograms showing the presence of S (top panel) and ΔPhe52 (lower panel) variants in the same allele. The wild-type sequences are GAA and TTCTTC, respectively.