Genotypes and serum concentrations of human alpha-1-antitrypsin “P” protein variants in a clinical population

• Published in: Journal of clinical pathology Vol. 60; no. 10; pp. 1124 - 1128
• Main Authors: Bornhorst, Joshua A, Calderon, Fernanda R O, Procter, Melinda, Tang, Wei, Ashwood, Edward R, Mao, Rong
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd and Association of Clinical Pathologists 01.10.2007; BMJ; BMJ Publishing Group LTD; BMJ Group
• Subjects: AAT; alpha 1-Antitrypsin - blood; alpha 1-Antitrypsin - genetics; alpha 1-Antitrypsin Deficiency - blood; alpha 1-Antitrypsin Deficiency - genetics; alpha-1-antitrypsin; Biological and medical sciences; full gene sequencing; Gene Frequency; Genotype; Humans; IEF; Investigative techniques, diagnostic techniques (general aspects); isoelectric focusing; Isoelectric Focusing - methods; Medical sciences; Original; P variant; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Phenotype; Polymerase Chain Reaction - methods; Retrospective Studies; Human; Typing; Genetic variability; Enzyme; Genotype; Concentration; Protein; α1-Antitrypsin; Variant; Anatomic pathology; Population; Serum; Oxidoreductases; Glycine dehydrogenase (decarboxylating)
• ISSN: 0021-9746; 1472-4146
• DOI: 10.1136/jcp.2006.042762

Background: Alpha-1-antitrypsin (AAT) deficiency is a relatively common genetic disorder that can lead to the development of pulmonary disorders. Diagnosis of AAT deficiency is typically performed by isoelectric focusing (IEF) protein phenotyping in concert with determination of AAT serum concentration levels. The “P” phenotypic variant is associated with several known genetic variants that are found at unknown relative frequencies. Aims: To investigate the genetic variation of “P” alleles in patient samples. Methods: A DNA sequencing protocol for the full AAT coding region from serum was developed. Additionally, a retrospective evaluation of AAT concentrations in serum samples containing “P” allele IEF phenotype variants was undertaken. Results: “P” phenotypic variants are observed in ∼1 of every 900 samples received in the reference laboratory. Heterozygous “MP” allele samples exhibited a wide range of serum protein concentrations. Genotyping revealed the presence of the deleterious Plowell variant in six heterozygous MP samples, two heterozygous PZ samples, and one homozygous PP sample. A non-deleterious Pst albans variant was observed in a single MP sample. A novel heterozygous AAT M“P” variant, Psalt lake was identified, that did not exhibit a reduced AAT serum concentration. Conclusions: Genetic heterogeneity is present in clinical “P” phenotype variants identified by IEF, and the deleterious Plowell variant appears to be relatively common. Sequencing of “P” phenotype variants can provide useful clinical information, especially when the “P” phenotype variant is paired with a deficiency phenotype allele.