Mammalian Genome

, Volume 29, Issue 3–4, pp 281–298 | Cite as

Loss of the zona pellucida-binding protein 2 (Zpbp2) gene in mice impacts airway hypersensitivity and lung lipid metabolism in a sex-dependent fashion

  • Cynthia Kanagaratham
  • Victoria Chiwara
  • Bianca Ho
  • Sanny Moussette
  • Mina Youssef
  • David Venuto
  • Lucie Jeannotte
  • Guillaume Bourque
  • Juan Bautista de Sanctis
  • Danuta Radzioch
  • Anna K. Naumova
Article

Abstract

The human chromosomal region 17q12–q21 is one of the best replicated genome-wide association study loci for childhood asthma. The associated SNPs span a large genomic interval that includes several protein-coding genes. Here, we tested the hypothesis that the zona pellucida-binding protein 2 (ZPBP2) gene residing in this region contributes to asthma pathogenesis using a mouse model. We tested the lung phenotypes of knock-out (KO) mice that carry a deletion of the Zpbp2 gene. The deletion attenuated airway hypersensitivity (AHR) in female, but not male, mice in the absence of allergic sensitization. Analysis of the lipid profiles of their lungs showed that female, but not male, KO mice had significantly lower levels of sphingosine-1-phosphate (S1P), very long-chain ceramides (VLCCs), and higher levels of long-chain ceramides compared to wild-type controls. Furthermore, in females, lung resistance following methacholine challenge correlated with lung S1P levels (Pearson correlation coefficient 0.57) suggesting a link between reduced AHR in KO females, Zpbp2 deletion, and S1P level regulation. In livers, spleens and blood plasma, however, VLCC, S1P, and sphingosine levels were reduced in both KO females and males. We also find that the Zpbp2 deletion was associated with gain of methylation in the adjacent DNA regions. Thus, we demonstrate that the mouse ortholog of ZPBP2 has a role in controlling AHR in female mice. Our data also suggest that Zpbp2 may act through regulation of ceramide metabolism. These findings highlight the importance of phospholipid metabolism for sexual dimorphism in AHR.

Notes

Acknowledgements

The authors are grateful to Pamela Stroud, Amanda Baumholtz, and Wei Cui for technical assistance and Drs. Danielle Malo and Aimee Ryan for helpful discussion. This work was supported by funds from the Canadian Institutes of Health Research (to AKN and DR) and the Research Institute of the McGill University Health Centre (to AKN). DR is a member of Infectious Diseases and Immunity in Global Health Program, (IDIGH). VC has been a recipient of the Department of Human Genetics scholarship. CK has been a recipient of the Banting and Best Doctoral Training Award from CIHR.

Author contributions

CK contributed to study design, data collection, statistical analysis, and writing of the manuscript. VC contributed to data collection, data analysis, and writing the manuscript. MY, BH, and SM contributed to data collection and analysis. DV contributed to data analysis, interpretation and writing of the manuscript. LJ contributed to data collection. GB contributed to data analysis and interpretation. JBdS contributed to data collection and data analysis. DR contributed to study design, data interpretation and edited the manuscript. AKN contributed to study design, data collection, analysis, data interpretation, and wrote the manuscript. All authors reviewed the manuscript.

Compliance with ethical standards

Conflict of interest

Authors declare that they have no competing interest.

Supplementary material

335_2018_9743_MOESM1_ESM.docx (849 kb)
Supplementary material 1 (DOCX 848 KB)

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Authors and Affiliations

  • Cynthia Kanagaratham
    • 1
  • Victoria Chiwara
    • 1
  • Bianca Ho
    • 1
  • Sanny Moussette
    • 2
  • Mina Youssef
    • 1
  • David Venuto
    • 3
  • Lucie Jeannotte
    • 4
    • 5
  • Guillaume Bourque
    • 1
    • 3
  • Juan Bautista de Sanctis
    • 6
  • Danuta Radzioch
    • 1
    • 2
    • 7
    • 8
  • Anna K. Naumova
    • 1
    • 2
    • 9
  1. 1.Department of Human GeneticsMcGill UniversityMontrealCanada
  2. 2.The Research Institute of the McGill University Health CentreMontrealCanada
  3. 3.McGill University and Genome Quebec Innovation CentreMontrealCanada
  4. 4.Département de Biologie moléculaire, Biochimie medicale & Pathologie, Faculté de médecineUniversité LavalQuébecCanada
  5. 5.Centre de recherche sur le cancer de l’Université LavalCRCHU de Québec-Université LavalQuébecCanada
  6. 6.Institute of Immunology, Faculty of MedicineUniversidad Central de VenezuelaCaracasVenezuela
  7. 7.Division of Experimental Medicine, Faculty of MedicineMcGill UniversityMontrealCanada
  8. 8.Infectious Diseases and Immunity in Global Health Program (IDIGH)The Research Institute of the McGill University Health CentreMontrealCanada
  9. 9.Department of Obstetrics and GynecologyMcGill UniversityMontrealCanada

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