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Role of Cecr2 and Candidate Modifier Genes of Cecr2 in the Neural Tube Defect Exencephaly Open Access


Other title
Neural tube defect
Circling behavior
Modifier gene
Gene environment interaction
Environmental enrichment
Type of item
Degree grantor
University of Alberta
Author or creator
Leduc, Renee YM
Supervisor and department
McDermid, Heather (Biological Sciences)
Examining committee member and department
Berry, Fred (Medical Genetics)
King-Jones, Kirst (Biological Sciences)
Department of Biological Sciences
Molecular Biology and Genetics
Date accepted
Graduation date
Doctor of Philosophy
Degree level
Neurulation, the early developmental process that forms the rudiment of the brain and spinal cord, relies upon the intricate interplay of hundreds of genes in multiple genetic pathways within the appropriate environmental conditions. Neural tube defects (NTDs), common congenital birth defects in humans, arise when the process of neurulation is disrupted. Human NTDs are multifactorial disorders, which means that combinations of many genetic, epigenetic, and environmental factors interact in order for disease to manifest. Our mouse model of NTDs develops the perinatal lethal cranial NTD exencephaly (the murine equivalent of anencephaly in humans) when homozygous for a loss-of-function mutation in the ATP-dependent chromatin remodeling gene Cecr2. Much like in humans, manifestation of the exencephaly phenotype in Cecr2 mutant mice is dependent on multiple factors. Work in this thesis focused on identifying and characterizing the multifactorial nature of exencephaly in both Cecr2 mutant mice and in humans. A previously established incomplete penetrance of exencephaly in Cecr2 homozygous mutant mouse embryos is indicative of genetic and/or environmental changes that are contributing resistance to exencephaly. An updated penetrance analysis that I performed revealed a reduction in exencephaly penetrance, which demonstrated that genetic and/or environmental factors are changing over time. Previous work in our lab has shown that the penetrance of exencephaly in Cecr2 mutant mice is dependent on mouse strain, as Cecr2 mutant BALB/cCrl mice are susceptible to developing exencephaly but Cecr2 mutant FVB/N mice are resistant. This inter-strain variability suggests the presence of modifier genes, where the BALB/cCrl genetic background harbors susceptibility alleles and FVB/N harbors resistance alleles. Prior studies from the McDermid lab identified a modifier region in mouse chromosome 19 that contains at least two modifier loci, which contribute to the difference in exencephaly penetrance seen between Cecr2 mutant BALB/cCrl and FVB/N. I have further characterized the chromosome 19 modifier region and demonstrated that the two modifier loci are not additive, suggesting that the modifiers are involved in the same pathway or process. I then used whole exome sequencing of the two mouse strains to identify candidate modifier genes containing protein-coding variants that differed between the two strains. With this analysis, combined with previously generated data from whole genome microarrays, I produced a list of 26 candidate modifier genes that differ in expression and/or protein code between the two mouse strains. I showed via genetic analysis in the mouse that the top candidate gene, Arhgap19, is most likely not a Cecr2 modifier. The human homologue of CECR2 and the human homologues of the remaining candidate modifier genes were then sequenced in a cranial NTD cohort consisting of 156 probands. This study in humans identified protein-coding variants that were predicted to affect protein function in CECR2 and in 17 of the candidate modifier genes, as well as established DNMBP, MMS19, and TJP2 as top candidate NTD modifier genes. As an independent but related project, I also characterized a gene-environment interaction that resulted in circling behavior, a phenotype unrelated to NTDs, in male mice of a specific genetic cohort in our mouse colony. This study is the first to show that environmental enrichment in the form of running-wheels can induce abnormal behaviors in genetically susceptible mice. Additionally, I sought to characterize phenotypes due to homozygous mutation or knockdown of the Drosophila melanogaster homologue of Cecr2 (dikar) in an effort to produce a more tractable genetic model to study the molecular function of Cecr2. Results indicated that dikar is dispensible for normal fly development with no obvious phenotype due to loss of dikar. Overall, I have established the Cecr2 mutant mouse as a valuable model for studying the multifactorial nature of NTDs and have produced several novel candidate NTD genes in mice and humans. Important future work will be directed towards the functional characterization of protein-coding variants identified in the human cranial NTD cohort. In the event that a variant is shown to have a functional impact, expanded sequencing efforts of this variant or the gene it affects in additional NTD patients will aid in determining the relevance of such a gene in human NTD etiology.
This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for the purpose of private, scholarly or scientific research. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
Citation for previous publication
Kooistra, M.K., R.Y.M. Leduc, C.E. Dawe, N.A. Fairbridge, J. Rasmussen, J.H. Man, M. Bujold, D. Juriloff, K. King-Jones and H.E. McDermid. (2012). Strain-specific modifier genes of Cecr2-associated exencephaly in mice: genetic analysis and identification of differentially expressed candidate genes. Physiol. Genomics 44:35-46.

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