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


OBJECTIVE
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 approximately 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 P lowell variant in six heterozygous MP samples, two heterozygous PZ samples, and one homozygous PP sample. A non-deleterious P st albans variant was observed in a single MP sample. A novel heterozygous AAT M"P" variant, P salt 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 P lowell 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.
Bornhorst
Joshua A
JA
Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. jabornhorst@uams.edu
Calderon
Fernanda R O
FR
Procter
Melinda
M
Tang
Wei
W
Ashwood
Edward R
ER
Mao
Rong
R
D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007525:Isoelectric Focusing / Q000379:methods; D010641:Phenotype; D016133:Polymerase Chain Reaction / Q000379:methods; D012189:Retrospective Studies; D000515:alpha 1-Antitrypsin / Q000097:blood / Q000235:genetics*; D019896:alpha 1-Antitrypsin Deficiency / Q000097:blood / Q000235:genetics*
C043392:SERPINA1 protein, human; D000515:alpha 1-Antitrypsin