| 1 | Epilepsia 2011 Mar 52: 423-32 |
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| PMID | 21269290 |
| Title | Epilepsy and the new cytogenetics. |
| Abstract | We set out to review the extent to which molecular karyotyping has overtaken conventional cytogenetics in applications related to epilepsy. Multiplex ligase-dependent probe amplification (MLPA) targeted to predetermined regions such as SCN1A and KCNQ2 has been effectively applied over the last half a decade, and oligonucleotide array comparative genome hybridization (array CGH) is now well established for genome-wide exploration of microchromosomal variation. Array CGH is applicable to the characterization of lesions present in both sporadic and familial epilepsy, especially where clinical features of affected cases depart from established syndromes. Copy number variants (CNVs) associated with epilepsy and a range of other syndromes and conditions can be recurrent due to nonallelic homologous recombination in regions of segmental duplication. The most common of the recurrent microdeletions associated with generalized epilepsy are typically seen at a frequency of ? 1% at 15q13.3, 16p13.11, and 15q11.2, sites that also confer susceptibility for intellectual disability, autism, and schizophrenia. Incomplete penetrance and variable expressivity confound the established rules of cytogenetics for determining the pathogenicity for novel CNVs; however, as knowledge is gained for each of the recurrent CNVs, this is translated to genetic counseling. CNVs play a significant role in the susceptibility profile for epilepsies, with complex genetics and their comorbidities both from the "hotspots" defined by segmental duplication and elsewhere in the genome where their location and size are often novel. |
| SCZ Keywords | schizophrenia |
| 2 | Mol. Psychiatry 2011 Feb 16: 184-92 |
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| PMID | 20038948 |
| Title | A genome-wide survey of human short-term memory. |
| Abstract | Recent advances in the development of high-throughput genotyping platforms allow for the unbiased identification of genes and genomic sequences related to heritable traits. In this study, we analyzed human short-term memory, which refers to the ability to remember information over a brief period of time and which has been found disturbed in many neuropsychiatric conditions, including schizophrenia and depression. We performed a genome-wide survey at 909?622 polymorphic loci and report six genetic variations significantly associated with human short-term memory performance after genome-wide correction for multiple comparisons. A polymorphism within SCN1A (encoding the ? subunit of the type I voltage-gated sodium channel) was replicated in three independent populations of 1699 individuals. Functional magnetic resonance imaging during an n-back working memory task detected SCN1A allele-dependent activation differences in brain regions typically involved in working memory processes. These results suggest an important role for SCN1A in human short-term memory. |
| SCZ Keywords | schizophrenia |
| 3 | Trends Pharmacol. Sci. 2014 Mar 35: 113-8 |
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| PMID | 24439681 |
| Title | Therapeutic potential of Na(V)1.1 activators. |
| Abstract | Sodium channel inhibitors have been developed and approved as drugs to treat a variety of indications. By contrast, sodium channel activators have not previously been considered relevant in a therapeutic setting owing to their high risk of toxicity and side effects. Here we present an opinion that selective activators of the Na(V)1.1 sodium channel may hold therapeutic potential for diseases such as epilepsy, schizophrenia, and Alzheimer's disease. Central to this novel avenue of sodium channel drug discovery is that fact that Na(V)1.1 comprises the majority of the sodium current in specific inhibitory interneurons. Conversely, it plays only a modest role in excitatory neurons owing to the high redundancy of other types of sodium channels in these cells. We discuss the biological background and rationale and present reflections on how to identify activators of Na(V)1.1. |
| SCZ Keywords | schizophrenia |