Making a mouse model for schizophrenia: Using the mouse to model the schizophrenia susceptibility gene ZNF804A

Al-Janabi, Tamara 2012. Making a mouse model for schizophrenia: Using the mouse to model the schizophrenia susceptibility gene ZNF804A. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Schizophrenia is a complex disorder, with several genes putatively associated with the pathogenesis of the disorder. A large genome-wide association study (O’Donovan et al. 2008) identified ZNF804A as a candidate gene for schizophrenia (meta-analysis p = 1.61 x 10-7). The association of the gene with schizophrenia (and bipolar disorder) has since been successfully replicated several times, confirming the association (Riley et al., 2010; Steinberg et al., 2010; Zhang et al., 2010, Williams et al., 2011). The aim of this thesis is to create and provide preliminary assessments of a mouse model of the murine form of ZNF804A, Zfp804a. A mutagenised DNA archive derived from mice treated with N-ethyl-N-nitrosourea (ENU) held at the MRC Mammalian Genetics Unit, Harwell, was screened for mutations in Zfp804a. Two mutations (C59X and C417Y) were selected for re-derivation based upon the estimated impact upon the protein. The mutations were backcrossed onto a C57Bl/6J background for three successive generations using a panel of genetic markers to aid selection for the highest level of C57Bl/6J congenicity (and therefore speed up the backcrossing process). G4 mice were tested in the study. Preliminary assessments of the fourth generation intercross cohort revealed, most notably, that the mice breed well, have no gross physical deficits and that male Zfp804aC59X/C59X mutants appeared less anxious than other groups in the elevated plus maze and performed better than other groups on the RotaRod. Initial indications show that Zfp804a may indeed influence behaviour and cognition however further work is necessary to expand upon these findings with larger samples.

Item Type:	Thesis (PhD)
Status:	Unpublished
Schools:	Medicine
Subjects:	R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
Uncontrolled Keywords:	Zfp804a, ZNF804A, mouse model, schizophrenia, GWAS, behavioural genetics, ENU, mutation screen, anxiety, Rotarod, elevated plus maze, locomotor activity, open field, Phenotyper Home Cage Environment.
Date of First Compliant Deposit:	30 March 2016
Last Modified:	19 Mar 2016 23:12
URI:	https://orca.cardiff.ac.uk/id/eprint/42404

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