Article

Characterization of mutations in the genedoublecortin in patients with double cortex syndrome

Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
Annals of Neurology (Impact Factor: 11.91). 03/1999; 45(2):146-53. DOI: 10.1002/1531-8249(199902)45:2<146::AID-ANA3>3.0.CO;2-N
Source: PubMed

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.

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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
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    • "An essential factor for the development of the embryonic brain and nervous system is a protein called Doublecortin (dcx). Mutations in this gene in mammalian systems result in disruption of cortical neuronal migration [24]. An orthologous cDNA to dcx was identified as a library specific gene. "
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    • "Its presence in the tips of neurites of apparently non-migratory yet immature neurons suggest an additional role in neurite development [24]. Mutation in the human DCX gene causes a characteristic defect in cortical layering, the name-giving doublecortex [25], [26]. "
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    PLoS ONE 01/2010; 5(1):e8809. DOI:10.1371/journal.pone.0008809 · 3.23 Impact Factor
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