Characterization of mutations in the gene doublecortin in patients with double cortex syndrome

ArticleinAnnals of Neurology 45(2):146-53 · March 1999with7 Reads
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.
    • "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 (CouillardDespres 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). "
    [Show abstract] [Hide abstract] 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.
    Full-text · Article · Sep 2015
    • "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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    Article · May 2013
    • "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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    Article · Mar 2011
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