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Denmark Hill, United Kingdom

Hill M.J.,Queens University of Belfast | Hill M.J.,Center for the Cellular Basis of Behaviour | Reynolds G.P.,Queens University of Belfast
Pharmacogenomics | Year: 2011

Background: Genetic variation in the promoter region of HTR2C encoding for the 5-HT2C receptor is associated with antipsychotic-induced weight gain. Several studies have investigated the regulatory potential of associated variants using gene-reporter systems. Establishing associated polymorphisms as causal variants may aid in the identification of the molecular mechanisms of phenotypic variation. Aims & methods: To this end we examined the binding of nuclear factors from rat hypothalamus to two polymorphisms in HTR2C, rs3813929 (-759C/T) and rs518147 (-697C/G) using electromobility shift assays. For rs518147, allele-specific RNA folding was also investigated. Results: Both polymorphisms bound nuclear factors, identifying the sequence fragments as regulatory elements. Importantly, rs3813929 (-759C/T) altered DNA-â€"protein interactions with the weight gain-resistant allele abolishing the formation of two complexes. The formation of allele-specific RNA loops was also observed for rs518147. Conclusion: These data establish rs3813929 (-759C/T) as a functional polymorphism and suggest disruption of DNA-â€"protein interactions as a mechanism by which HTR2C expression is perturbed leading to an influence on antipsychotic-induced weight gain. Original submitted 8 December 2010; Revision submitted 25 January 201. © 2011 Future Medicine Ltd.


Blom T.,Finnish National Institute for Health and Welfare | Blom T.,Institute for Molecular Medicine Finland | Schmiedt M.-L.,Finnish National Institute for Health and Welfare | Schmiedt M.-L.,Institute for Molecular Medicine Finland | And 11 more authors.
DMM Disease Models and Mechanisms | Year: 2013

Both CLN1 and CLN5 deficiencies lead to severe neurodegenerative diseases of childhood, known as neuronal ceroid lipofuscinoses (NCLs). The broadly similar phenotypes of NCL mouse models, and the potential for interactions between NCL proteins, raise the possibility of shared or convergent disease mechanisms. To begin addressing these issues, we have developed a new mouse model lacking both Cln1 and Cln5 genes. These double-knockout (Cln1/5 dko) mice were fertile, showing a slight decrease in expected Mendelian breeding ratios, as well as impaired embryoid body formation by induced pluripotent stem cells derived from Cln1/5 dko fibroblasts. Typical disease manifestations of the NCLs, i.e. seizures and motor dysfunction, were detected at the age of 3 months, earlier than in either single knockout mouse. Pathological analyses revealed a similar exacerbation and earlier onset of disease in Cln1/5 dko mice, which exhibited a pronounced accumulation of autofluorescent storage material. Cortical demyelination and more pronounced glial activation in cortical and thalamic regions was followed by cortical neuron loss. Alterations in lipid metabolism in Cln1/5 dko showed a specific increase in plasma phospholipid transfer protein (PLTP) activity. Finally, gene expression profiling of Cln1/5 dko cortex revealed defects in myelination and immune response pathways, with a prominent downregulation of a-synuclein in Cln1/5 dko mouse brains. The simultaneous loss of both Cln1 and Cln5 genes might enhance the typical pathological phenotypes of these mice by disrupting or downregulating shared or convergent pathogenic pathways, which could potentially include interactions of CLN1 and CLN5. © 2013. Published by The Company of Biologists Ltd.


Uwanogho D.A.,Center for the Cellular Basis of Behaviour | Yasin S.A.,Center for the Cellular Basis of Behaviour | Starling B.,Center for the Cellular Basis of Behaviour | Price J.,Center for the Cellular Basis of Behaviour
Gene | Year: 2010

Mammalian genomes are highly complex, with neighbouring genes arranged in divergent, convergent, tandem, antisense, and interleaving fashions. Despite the vast genomic space, a substantial portion of human genes (∼ 10%) are arranged in a divergent, head-to-head fashion and controlled by bidirectional promoters. Here we define a small core bidirectional promoter that drives expression of the mouse genes Recql4, on one strand, and Lrrc14; a novel member of the LRR gene family, on the opposite strand. Regulation of Lrrc14 expression is highly complex, involving multiple promoters' and alternative splicing. Expression of this gene is predominately restricted to neural tissue during embryogenesis and is expressed in a wide range of tissues in the adult. © 2009 Elsevier B.V. All rights reserved.


Buonocore F.,Center for the Cellular Basis of Behaviour | Hill M.J.,Center for the Cellular Basis of Behaviour | Campbell C.D.,Center for the Cellular Basis of Behaviour | Campbell C.D.,Kings College London | And 7 more authors.
Human Molecular Genetics | Year: 2010

Cis-regulatory variation is considered to be an important determinant of human phenotypic variability, including susceptibility to complex disease. Recent studies have shown that the effects of cis-regulatory polymorphism on gene expression can differ widely between tissues. In the present study, we tested whether the effects of cis-regulatory variation can also differ between regions of the adult human brain. We used relative allelic expression to measure cis-effects on the RNA expression of five candidate genes for neuropsychiatric illness (ZNF804A, NOS1, RGS4, AKT1 and TCF4) across multiple discrete brain regions within individual subjects. For all five genes, we observed significant differences in allelic expression between brain regions in several individual subjects, suggesting regional differences in the effects of cis-regulatory polymorphism to be a common phenomenon. As well as highlighting an important caveat for studies of regulatory polymorphism in the brain, our findings indicate that it is possible to delineate brain areas in which cisregulatory variants are active. This may provide important insights into the fundamental biology of neuropsychiatric phenotypes with which such variants are associated. © The Author 2010. Published by Oxford University Press. All rights reserved.

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