Characterization of mutations in the gene doublecortin in patients with double cortex syndrome.
ABSTRACT Mutations in the X-linked gene doublecortin, which encodes a protein with no dear structural homologues, are found in pedigrees in which affected females show "double cortex" syndrome (DC; also known as subcortical band heterotopia or laminar heterotopia) and affected males show X-linked lissencephaly. Mutations in doublecortin also cause sporadic DC in females. To determine the incidence of doublecortin mutations in DC, we investigated a cohort of eight pedigrees and 47 sporadic patients with DC for mutations in the doublecortin open reading frame as assessed by single-stranded conformational polymorphism analysis. Mutations were identified in each of the eight DC pedigrees (100%), and in 18 of the 47 sporadic DC patients (38%). Identified mutations were of two types, protein truncation mutations and single amino acid substitution mutations. However, pedigrees with DC displayed almost exclusively single amino acid substitution mutations, suggesting that patients with these mutations may have less of a reproductive disadvantage versus those patients with protein truncation mutations. Single amino acid substitution mutations were tightly clustered in two regions of the open reading frame, suggesting that these two regions are critical for the function of the Doublecortin protein.
Article: The genetics of lissencephaly[Show abstract] [Hide abstract]
ABSTRACT: Lissencephaly is a spectrum of severe brain malformations caused by the failure of migrating neurons to reach optimal positions in the developing cerebral cortex. Several syndromes associated with lissencephaly have been characterized in recent years. Identification of the genetic basis of these disorders has brought fascinating insights into the mechanisms of brain development, as well as benefits to patients through improved molecular diagnosis and genetic counseling. This review explores the clinical presentation, radiological features, histological findings and molecular basis of lissencephaly with the aim of facilitating the selection and interpretation of gene tests in patients with 'smooth brain' phenotypes. © 2014 Wiley Periodicals, Inc.American Journal of Medical Genetics Part C Seminars in Medical Genetics 06/2014; 166(2). DOI:10.1002/ajmg.c.31402 · 3.54 Impact Factor
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ABSTRACT: During early brain development, NMDA receptors are involved in cell migration, neuritogenesis, axon guidance and synapse formation, but the mechanisms which regulate NMDA receptor density and function remain unclear. The kynurenine pathway of tryptophan metabolism includes an agonist (quinolinic acid) and an antagonist (kynurenic acid) at NMDA receptors and we have previously shown that inhibition of the pathway using the kynurenine-3-monoxygenase inhibitor Ro61-8048 in late gestation produces rapid changes in protein expression in the embryos and effects on synaptic transmission lasting until postnatal day 21 (P21). The present study sought to determine whether any of these effects are maintained into adulthood. After prenatal injections of Ro61-8048 the litter was allowed to develop to P60 when some offspring were euthanised and the brains removed for examination. Analysis of protein expression by western blotting revealed significantly reduced expression of the GluN2A subunit (32%) and the morphogenetic protein sonic hedgehog (31%), with a 29% increase in expression of doublecortin, a protein associated with neurogenesis. No changes were seen in mRNA abundance using qRT-PCR. Neuronal excitability was normal in the CA1 region of hippocampal slices but paired-pulse stimulation revealed less inhibition at short interpulse intervals. The amount of long-term potentiation was decreased by 49% in treated pups and recovery after low frequency stimulation was delayed. The results not only strengthen the view that basal, constitutive kynurenine metabolism is involved in normal brain development, but also show that changes induced prenatally can affect the brains of adult offspring and those changes are quite different from those seen previously at weaning (P21). Those changes may be mediated by altered expression of NMDAR subunits and sonic hedgehog.Neuroscience 09/2013; DOI:10.1016/j.neuroscience.2013.09.034 · 3.33 Impact Factor
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ABSTRACT: Epilepsy is a common and diverse set of chronic neurological disorders characterized by spontaneous, unprovoked, and recurrent epileptic seizures. Environmental factors and acquired disposition are proposed to play a role to the pathogenesis of epilepsy. Genetic factors are important contributors as well. Comparing to the phenotype of epilepsy caused by mutation of single gene on an autosome, the phenotype of X-linked epilepsy is more complex. X-linked epilepsy usually manifests as part of a syndrome or epileptic encephalopathy, and the variability of clinical manifestations of X-linked epilepsy may be attributed to several factors including the type of genetic mutation, methylation, X chromosome random inactivation, and mosaic distribution. As a result, it is difficult to establish the genotype-phenotype correlation, diagnostic tests, and genetic counseling. In this review, we provide an overview of the X-linked epilepsy including responsible loci and genes, the molecular biology, the associated complex phenotypes, and the interference factors. This information may provide us a better understanding of the pathogenesis of X-linked epilepsy and may contribute to clinical diagnosis and therapy of epilepsy.Molecular Neurobiology 11/2013; DOI:10.1007/s12035-013-8589-1 · 5.29 Impact Factor