Null Canada : A novel α 1 -antitrypsin allele with in cis variants Glu366Lys and Ile100Asn.

Autor: Chen S; Department of Pathology and Laboratory Medicine, St. Paul's Hospital, BC, Canada., DeMarco ML; Department of Pathology and Laboratory Medicine, St. Paul's Hospital, BC, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, BC, Canada; Centre for Heart Lung Innovation, University of British Columbia, BC, Canada., Estey MP; DynaLIFE Medical Labs, AB, Canada; Department of Laboratory Medicine and Pathology, University of Alberta, AB, Canada., Kyle B; DynaLIFE Medical Labs, AB, Canada; Department of Laboratory Medicine and Pathology, University of Alberta, AB, Canada., Parker ML; DynaLIFE Medical Labs, AB, Canada; Department of Laboratory Medicine and Pathology, University of Alberta, AB, Canada., Agbor TA; DynaLIFE Medical Labs, AB, Canada; Department of Laboratory Medicine and Pathology, University of Alberta, AB, Canada., Kawada P; Division of Pediatric Gastroenterology & Nutrition, Department of Pediatrics, University of Alberta, AB, Canada., Speevak M; Department of Laboratory Medicine and Genetics, Trillium Health Partners, ON, Canada., Nelson TN; Department of Pathology and Laboratory Medicine, University of British Columbia, BC, Canada; Department of Pathology and Laboratory Medicine, BC Children's & BC Women's Hospitals, BC, Canada., Mattman A; Department of Pathology and Laboratory Medicine, St. Paul's Hospital, BC, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, BC, Canada. Electronic address: amattman@providencehealth.bc.ca.
Jazyk: angličtina
Zdroj: Clinical biochemistry [Clin Biochem] 2020 May; Vol. 79, pp. 23-27. Date of Electronic Publication: 2020 Feb 19.
DOI: 10.1016/j.clinbiochem.2020.02.013
Abstrakt: Background: α 1 -Antitrypsin (A1AT) deficiency predisposes patients to pulmonary disease due to inadequate protection against human neutrophil elastase released during inflammatory responses. A1AT deficiency is caused by homozygosity or compound heterozygosity for A1AT variants; individuals with A1AT deficiency most commonly have at least one Z variant allele (c.1096G > A (Glu366Lys)). Null variants that result in complete absence of A1AT in the plasma are much rarer. With one recent exception, all reported A1AT variants are characterized by a single pathogenic variant.
Case: An 8 years old patient from Edmonton, Alberta, Canada, was investigated for A1AT deficiency. His A1AT phenotype was determined to be M (wild type)/Null by isoelectric focusing (IEF) but M/Z by targeted genotyping. Gene sequencing revealed two heterozygous variants: Z and Ile100Asn (c.299 T > A). The Ile100Asn substitution is predicted to disrupt the secondary structure of an α-helix in which it resides and the neighbouring tertiary structure, resulting in intracellular degradation of A1AT prior to hepatocyte secretion.
Methods: Family testing was conducted to verify potential inheritance of an A1AT allele carrying the two mutations in cis, as this arrangement of the mutations would explain "Z" detection by genotyping but not by IEF. Molecular modeling was used to assess the effect of the variants on A1AT structure and stability.
Discussion: Carrier status for a novel variant Null Canada with in cis mutations (c.[299 T > A;1096G > A], p.[(Ileu100Asn;Glu366Lys)]) was confirmed. A sibling was identified as having A1AT deficiency on the basis of compound heterozygosity for two alleles: Null Canada and the common Z allele. A separate pedigree from the Maritimes was subsequently recognized as carrying Null Canada .
Conclusion: In cis mutations such as Null Canada may be more common than previously described due to failure to detect such mutations using historical testing methods. Combined approaches that include gene sequencing and segregation studies allow recognition of rare A1AT variants, including in cis mutations.
(Copyright © 2020 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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