Gleeson, J.G. et al. Characterization of mutations in the gene doublecortin in patients with double cortex syndrome. Ann. Neurol. 45, 146-153

Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
Annals of Neurology (Impact Factor: 9.98). 03/1999; 45(2):146-53. DOI: 10.1002/1531-8249(199902)45:2<146::AID-ANA3>3.0.CO;2-N
Source: PubMed


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.

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    • "Lastly, three proteins involved in the cell cycle (PCNA), and early neuronal maturation, differentiation and migration (doublecortin, [DCX] and sonic hedgehog, [Shh]) were examined. DCX is a microtubule-associated protein expressed in cells early after mitosis (Couillard- Despres et al., 2005) and which may be involved in disorders of neocortical and hippocampal development (Gleeson et al., 1999; Nacher et al., 2001; Corbo et al., 2002). Shh protein is important in the formation of morphogenetic gradients (Palma et al., 2005; Traiffort et al., 2010) and the generation of functional synaptic contacts (Angot et al., 2008; Hor and Tang, 2010) but it does persist in the adult CNS (Traiffort et al., 1998; Charytoniuk et al., 2002; Ahn and Joyner, 2005; Dellovade et al., 2006). "
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    ABSTRACT: Glutamate receptors sensitive to N-methyl-D-aspartate (NMDA) are involved in embryonic brain development but their activity may be modulated by the kynurenine pathway of tryptophan metabolism which includes an agonist (quinolinic acid) and an antagonist (kynurenic acid) at these receptors. Our previous work has shown that prenatal inhibition of the pathway produces abnormalities of brain development. In the present study kynurenine and probenecid (both 100mg/kg, doses known to increase kynurenic acid levels in the brain) were administered to female Wistar rats on embryonic days E14, E16 and E18 of gestation and the litter was allowed to develop to post-natal day P60. Western blotting revealed no changes in hippocampal expression of several proteins previously found to be altered by inhibition of the kynurenine pathway including the NMDA receptor subunits GluN1, GluN2A and GluN2B, as well as doublecortin, Proliferating Cell Nuclear Antigen (PCNA), sonic hedgehog and unco-ordinated (unc)-5H1 and 5H3. Mice lacking the enzyme kynurenine-3-monoxygenase (KMO) also showed no changes in hippocampal expression of several of these proteins or the 70kDa and 100kDa variants of Disrupted in Schizophrenia-1 (DISC1). Electrical excitability of pyramidal neurons in the CA1 region of hippocampal slices was unchanged, as was paired-pulse facilitation and inhibition. Long-term potentiation was decreased in the kynurenine-treated rats and in the KMO(-/-) mice, but galantamine reversed this effect in the presence of nicotinic receptor antagonists, consistent with evidence that it can potentiate glutamate at NMDA receptors. It is concluded that interference with the kynurenine pathway in utero can have lasting effects on brain function of the offspring, implying that the kynurenine pathway is involved in the regulation of early brain development.
    Neuroscience 09/2015; 310. DOI:10.1016/j.neuroscience.2015.09.022 · 3.36 Impact Factor
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    • "Because of its 5 polycystic kidney domains, it has been suggested that this gene plays a role in cell adhesion, and is therefore consistent with its being involved in neural cell adhesion [39]. DCDC2 is one of an eleven-member group of proteins distinguished by the presence of doublecortin domains [40]–[42]. The doublecortin domain is critical for binding to and stabilizing microtubules [42], and two members of this family (DCX and DCLK) have been shown to interactively affect axon outgrowth and neocortical neuronal migration [43], [44]. Overexpression of the N- terminal p23 domain of DYX1C1 protein can interact with Hsp70, Hsp90 and CHIP, all of which point toward its role in degradation of unfolded proteins [45], [46]. "
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    ABSTRACT: Developmental dyslexia is a language learning disorder that affects approximately 4-10% of the population. A number of candidate dyslexia susceptibility genes have been identified, including DCDC2 and KIAA0319 on Chromosome (Chr) 6p22.2 and DYX1C1 on Chr 15q21. Embryonic knockdown of the function of homologs of these genes in rat neocortical projection cell progenitors by in utero electroporation of plasmids encoding small hairpin RNA (shRNA) revealed that all three genes disrupted neuronal migration to the neocortex. Specifically, this disruption would result in heterotopia formation (Dyx1c1 and Kiaa0319) and/or overmigration past their expected laminar location (Dyx1c1 and Dcdc2). In these experiments, neurons normally destined for the upper neocortical laminæ were transfected on embryonic day (E) 15.5, and we designed experiments to test whether these migration phenotypes were the result of targeting a specific type of projection neuron. We transfected litters with Dcdc2 shRNA, Dyx1c1 shRNA, Kiaa0319 shRNA, or fluorescent protein (as a control) at each of three gestational ages (E14.5, E15.5, or E16.5). Pups were allowed to come to term, and their brains were examined at 3 weeks of age for the position of transfected cells. We found that age of transfection did not affect the percentage of unmigrated neurons-transfection with Kiaa0319 shRNA resulted in heterotopia formation at all three ages. Overmigration of neurons transfected with Dcdc2 shRNA, while present following transfections at the later ages, did not occur following E14.5 transfections. These results are considered in light of the known functions of each of these candidate dyslexia susceptibility genes.
    PLoS ONE 05/2013; 8(5):e65179. DOI:10.1371/journal.pone.0065179 · 3.23 Impact Factor
    • "Patients with DCX mutations present a rudimentary four layered cerebral cortex, probably caused by a severely disrupted cortical migration (Gleeson et al. 1999b). In hemizygous DCX mutant male mice, viability severely decreases during both neonatal period and beyond, and the majority of the increased mortality in the mutant male mice occurs in the first few days after birth (Corbo et al. 2002). "
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    ABSTRACT: In this study, we observed neuroblast differentiation in the somatosensory cortex (SSC) and hippocampal CA1 region (CA1), which is vulnerable to oxidative stress, of the mouse at various early postnatal days (P) 1, 7, 14, and 21 using doublecortin (DCX, a marker for neuroblasts). Cresyl violet and NeuN (Neuronal Nuclei) staining showed development of layers as well as neurons in the SSC and CA1. At P1, DCX-positive neuroblasts expressed strong DCX immunoreactivity in both the SSC and CA1. Thereafter, DCX immunoreactivity was decreased with time. At P7, many DCX-immunoreactive neuroblasts were well detected in the SSC and CA1. At P14, some DCX-positive neuroblasts were found in the SSC and CA1: The immunoreactivity was weak. At P21, DCX immunoreactivity was hardly found in cells in the SSC and CA1. These results suggest that DCX-positive neuroblasts were significantly decreased in the mouse SSC and CA1 from P14.
    Cellular and Molecular Neurobiology 03/2011; 31(5):729-36. DOI:10.1007/s10571-011-9670-9 · 2.51 Impact Factor
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