Human Molecular Genetics Advance Access published online on July 6, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddh203
© 2004 by Oxford University Press
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1 Neurobiology and Development and Genetics Programmes, The Babraham Institute, Babraham, Cambridge, CB2 4AT, United Kingdom
* To whom correspondence should be addressed. E-mail: lawrence.wilkinson{at}bbsrc.ac.uk.
Recent work has indicated altered emotional functioning in Turner's syndrome subjects (45,XO). We examined the role of X-chromosome deficiency on fear reactivity in X-monosomic mice (39,XO), and found that they exhibited anxiogenic behaviour relative to normal females (40,XX). A molecular candidate for this effect is Steroid sulfatase (Sts) as this is located in the pseudoautosomal region (PAR) of the X-chromosome and consequently is normally biallelically expressed. Additionally, the steroid sulfatase enzyme (STS) is putatively linked to fear reactivity by an effect on GABAA receptors via the action of neurosteroids. Real-Time PCR demonstrated that levels of Sts mRNA were reduced by half in the brains of 39,XO mice compared to 40,XX, and that expression levels of a number of GABAA subunits previously shown to be important components of fear processing (Gabra3, Gabra1 and Gabrg2) were also altered. However, 40,XY*X mice, in which the Y*X is a small chromosome comprising of a complete PAR and a small non-PAR segment of the X-chromosome, exhibited the same pattern of fear reactivity behaviour as 39,XO animals, but equivalent expression levels of Sts, Gabra1, Gabra3, and Gabrg2 to 40,XX females. This showed that although Sts may cause alterations in GABAA subunit expression, these changes do not result in increased fear reactivity. This suggests an alternative X-chromosome gene, that escapes inactivation, is responsible for the differences in fear reactivity between 39,XO and 40,XX mice. These findings inform the Turner's syndrome data, and point to novel genetic mechanisms that may be of general significance to the neurobiology of fear.
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Effects on fear reactivity in XO mice are due to haploinsufficiency of a non-PAR X gene: implications for emotional function in Turner's syndrome
2 MRC National Institute of Medical Research, Mill Hill, London, NW7 1AA, United Kingdom
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