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Biomedical subjects

A R Isles

Publications and source records attributed to A R Isles.

4 recordsLinked to original sources
PubMed2006

Modes of imprinted gene action in learning disability.

BACKGROUND: It is now widely acknowledged that there may be a genetic contribution to learning disability and neuropsychiatric disorders, stemming from evidence provided by family, twin and adoption studies, and from explicit syndromic conditions. Recently it has been recognized that in some cases the presentation of genetic syndromes (or discrete aspects of disorders) is dependent on the sex of the transmitting parent. Such 'parent-of-origin effects' can be explained by a number of genetic mechanisms, a predominant one of which is genomic imprinting. Genomic imprinting refers to the parent of origin-specific epigenetic marking of an allele of a gene, such that for some genes it is mainly the maternally inherited allele only that is expressed, whereas for others expression occurs mainly from the paternal copy. METHODS: Here we discuss the contribution of imprinted genes to mental dysfunction and learning disability, using clinical examples of association studies and explicit imprinting disorders (with particular emphasis to Angelman and Prader-Willi syndromes), and evidence from animal work. RESULTS: Clinical and animal studies strongly suggest that imprinted genes contribute to brain functioning, and when the genes or epigenetic processes are disrupted, this can give rise to neuropsychiatric problems. Another system to which imprinted genes provide a large contribute is the placenta and foetal development. Epidemiological studies suggest that this is also a key area in which dysregulation can give rise to learning difficulties. CONCLUSIONS: Disruption of imprinted genes, or the epigenetic processes controlling them, can contribute to learning disability. These effects can be divided into two types: direct effects, such as those seen in explicit imprinting disorders such as Angelman and Prader-Willi syndromes, and indirect effects as manifest via changes in foetal programming.

Animals↗
PubMed2001

Conditional ablation of neurones in transgenic mice.

Conditional targeted ablation of specific cell populations in living transgenic animals is a very powerful strategy to determine cell functions in vivo. This approach would be of particular value to study the functions of distinct neuronal populations; however, the transgene of choice for conditional cell ablation studies in mice, the herpes simplex virus thymidine kinase gene, cannot be used to ablate neurones as its principal mode of action relies on cell proliferation. Here we report that expression of the E.coli nitroreductase gene (Ntr) and metabolism of the prodrug CB1954 (5-aziridin-1-yl-2-4-dinitrobenzamide) to its cytotoxic derivative can be used to conditionally and acutely ablate specific neuronal populations in vivo. As proof of principal, we have ablated olfactory and vomeronasal receptor neurones by expressing Ntr under the control of the olfactory marker protein (OMP) gene promoter. We demonstrate that following CB1954 administration, olfactory and vomeronasal receptor neurones expressing the transgene were selectively eliminated from the olfactory epithelium (OE), and projections to the olfactory bulb (OB) were lost. The functional efficacy of cell ablation was demonstrated using a highly sensitive behavioural test to show that ablated mice had lost the olfactory ability to discriminate distinct odors and were consequently rendered anosmic. Targeted expression of Ntr to specific neuronal populations using conventional transgenes, as described here, or by "knock-in" gene targeting using embryonic stem cells may be of significant value to address the functions of distinct neuronal populations in vivo.

Animals↗
PubMed2001

Imprinted genes and mental dysfunction.

There is a rapidly accumulating body of evidence from family, adoption and twin studies suggestive of a genetic component to many common mental disorders. In some cases, the transmission of abnormalities has been shown to be dependent upon the sex of the parent from whom they are inherited. Such 'parent-of-origin effects' may be explained by a number of genetic mechanisms, one of which is 'genomic imprinting'. In imprinted genes one allele is silenced according to its parental origin. This in turn means that imprinted traits are passed down the maternal or paternal line, in contrast to the more frequent Mendelian mode of inheritance that is indifferent to the parental origin of the allele. In the present review, we survey the evidence for the influence of imprinted genes on a number of mental disorders, ranging from explicit imprinted conditions, where in some cases abnormalities have been mapped to particular gene candidates, to examples where the evidence for parent-of-origin effects is less strong. We also consider, briefly, the wider implications of imprinted effects on mental dysfunction, in particular with respect to evolutionary pressures on mammalian brain development and function.

Angelman Syndrome↗