The PIG‐A gene mutation assay in human biomonitoring and disease

Abstract

The blood cell phosphatidylinositol glycan class A (PIG‐A) gene mutation assay has been extensively researched in rodents for in vivo mutagenicity testing and is now being investigated in humans. The PIG‐A gene is involved in glycosyl phosphatidylinositol (GPI)‐anchor biosynthesis. A single mutation in this X‐linked gene can lead to loss of membrane‐bound GPI anchors, which can be enumerated via corresponding GPI‐anchored proteins (e.g., CD55) using flow cytometry. The studies published to date by different research groups demonstrate a remarkable consistency in PIG‐A mutant frequencies. Moreover, with the low background level of mutant erythrocytes in healthy subjects (2.9–5.56 × 10−6 mutants), induction of mutation post genotoxic exposure can be detected. Cigarette smoking, radiotherapy, and occupational exposures, including lead, have been shown to increase mutant levels. Future applications of this test include identifying new harmful agents and establishing new exposure limits. This mutational monitoring approach may also identify individuals at higher risk of cancer development. In addition, identifying protective agents that could mitigate these effects may reduce baseline somatic mutation levels and such behaviors can be encouraged. Further technological progress is required including establishing underlying mechanisms of GPI anchor loss, protocol standardization, and the development of cryopreservation methods to improve GPI‐anchor stability over time. If successful, this assay has the potential be widely employed, for example, in rural and low‐income countries. Here, we review the current literature on PIG‐A mutation in humans and discuss the potential role of this assay in human biomonitoring and disease detection.

PIGA Mutations and Glycosylphosphatidylinositol Anchor Dysregulation in Polyposis-Associated Duodenal Tumorigenesis

“…PIGA function cannot apparently be compensated for by any other member of the enzyme complex and thus loss of PIGA manifests in a deregulation of GPI-anchored proteins. GPI-anchored proteins and components of the GPI anchor biosynthesis pathway including PIGA are prognostic biomarkers in cancer ( 16 ). The ease of identifying PIGA mutant cells by flow cytometry ( 15 ) has led to the development of routine flow-based mutation detection assays for PNH and for mutagenicity in drug safety assessment ( 16 ).…”

“…GPI-anchored proteins and components of the GPI anchor biosynthesis pathway including PIGA are prognostic biomarkers in cancer ( 16 ). The ease of identifying PIGA mutant cells by flow cytometry ( 15 ) has led to the development of routine flow-based mutation detection assays for PNH and for mutagenicity in drug safety assessment ( 16 ).…”