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

Gleeson, Joseph G.; Minnerath, Sharon R.; Fox, Jeremy W.; Allen, Kristina M.; Luo, Robert; Hong, Susan E.; Berg, Michael J.; Kuzniecky, Ruben; Reitnauer, Pamela J.; Borgatti, Renato; Mira, Alberto; Guerrini, Renzo; Holmes, Gregory L.; Rooney, Cynthia M.; Berkovic, Samuel F.; Scheffer, Ingrid E.; Cooper, Edward C.; Ricci, Stefano; Cusmai, Raffaella; Crawford, Thomas O.; Leroy, Robert; Andermann, Eva; Wheless, James W.; Dobyns, William B.; Ross, M. Elizabeth; Walsh, Christopher A.

doi:10.1002/1531-8249(199902)45:2<146::aid-ana3>3.0.co;2-n

Cited by 158 publications

(87 citation statements)

References 17 publications

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“…Under such a hypothesis, one might expect that a truly protein-null human allele would be associated with a mild phenotype such as that of the mouse. However, the fact that numerous mutant human alleles of DCX have been sequenced, some of which represent severe truncations that are likely to be protein-null (Gleeson et al, 1999b), argues against such a possibility.…”

Section: Discussionmentioning

confidence: 99%

Doublecortin Is Required in Mice for Lamination of the Hippocampus But Not the Neocortex

et al. 2002

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Doublecortin (DCX) is a microtubule-associated protein that is required for normal neocortical and hippocampal development in humans. Mutations in the X-linked human DCX gene cause gross neocortical disorganization (lissencephaly or "smooth brain") in hemizygous males, whereas heterozygous females show a mosaic phenotype with a normal cortex as well as a second band of misplaced (heterotopic) neurons beneath the cortex ("double cortex syndrome"). We created a mouse carrying a targeted mutation in the Dcx gene. Hemizygous male Dcx mice show severe postnatal lethality; the few that survive to adulthood are variably fertile. Dcx mutant mice show neocortical lamination that is largely indistinguishable from wild type and show normal patterns of neocortical neurogenesis and neuronal migration. In contrast, the hippocampus of both heterozygous females and hemizygous males shows disrupted lamination that is most severe in the CA3 region. Behavioral tests show defects in context and cued conditioned fear tests, suggesting that deficits in hippocampal learning accompany the abnormal cytoarchitecture.

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Section: Discussionmentioning

confidence: 99%

Doublecortin Is Required in Mice for Lamination of the Hippocampus But Not the Neocortex

et al. 2002

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“…1,4,13,15,16 LIS and SBH are usually more severe anteriorly in patients with DCX mutations, although in the most severe malformations this may not be evident. This has been described as an anterior greater than posterior (A > P) gradient, which differs from the P > A gradient seen in LIS patients with LIS1 deletions or mutations.…”

Section: Introductionmentioning

confidence: 95%

“…[6][7][8][9][10] Mutations of DCX have been detected in males with isolated lissencephaly sequence (ILS), 11 and in females with SBH. 4,[12][13][14][15] although rare examples of males with SBH 16 and females with lissencephaly 17 have been reported.…”

Section: Introductionmentioning

confidence: 99%

“…11 Mutation analysis of DCX has been reported by our group and others in sporadic patients with LIS or SBH, with mutation detection frequencies of 12% in ILS 11 and 38% to 90% in SBH. 12,13,19 The large difference between the studies probably results from phenotypic heterogeneity and different inclusion criteria. In this study, we performed comprehensive mutation analysis of DCX in a large series of sporadic SBH females and ILSX/SBH families by direct PCR sequencing.…”

Section: Introductionmentioning

confidence: 99%

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Mutation analysis of the DCX gene and genotype/phenotype correlation in subcortical band heterotopia

et al. 2001

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Subcortical band heterotopia (SBH) comprises part of a spectrum of phenotypes associated with classical lissencephaly (LIS). LIS and SBH are caused by alterations in at least two genes: LIS1 (PAFAH1B1) at 17p13.3 and DCX (doublecortin) at Xq22.3-q23. DCX mutations predominantly cause LIS in hemizygous males and SBH in heterozygous females, and we have evaluated several families with LIS male and SBH female siblings. In this study, we performed detailed DCX mutation analysis and genotype-phenotype correlation in a large cohort with typical SBH. We screened 26 sporadic SBH females and 11 LIS/SBH families for DCX mutations by direct sequencing. We found 29 mutations in 22 sporadic patients and 11 pedigrees, including five deletions, four nonsense mutations, 19 missense mutations and one splice donor site mutation. The DCX mutation prevalence was 84.6% (22 of 26) in sporadic SBH patients and 100% (11 of 11) in SBH pedigrees. Maternal germline mosaicism was found in one family. Significant differences in genotype were found in relation to band thickness and familial vs sporadic status. European Journal of Human Genetics (2001) 9, 5-12.

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“…2,3,11 -13 For both the LIS1 and DCX genes, mutations that abolish function such as entire gene deletions, nonsense, frameshift and splicing mutations generally result in a more severe phenotype, while missense mutations tend to result in the milder phenotypes. 9,10,13,14 Intragenic deletions of the LIS1 and DCX genes also result in lissencephaly, but the frequency of these types of mutation as well as the associated disease severity has not been well characterized. Intragenic deletion mutations of the LIS1 gene, detected by Southern blot, have previously been found to account for approximately 8% of diseasecausing mutations.…”

Section: Introductionmentioning

confidence: 99%

Intragenic deletions and duplications of the LIS1 and DCX genes: a major disease-causing mechanism in lissencephaly and subcortical band heterotopia

et al. 2008

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Classical lissencephaly, or isolated lissencephaly sequence (ILS), and subcortical band heterotopia (SBH) are neuronal migration disorders associated with severe mental retardation and epilepsy. Abnormalities of the LIS1 and DCX genes are implicated in the majority of patients with these disorders and account for approximately 75% of patients with ILS, whereas mutations of DCX account for 85% of patients with SBH. The molecular basis of disease in patients with ILS and SBH, in whom no abnormalities have been identified, has been questioned. We studied a series of 83 patients with ILS, SBH or pachygyria, in whom no abnormalities of the LIS1 or DCX genes had been identified, for intragenic deletions and duplications by multiplex ligation-dependent probe amplification (MLPA). In 52 patients with ILS, we identified 12 deletions and 6 duplications involving the LIS1 gene (35%), with the majority resulting in grade 3 lissencephaly. Three deletions of the DCX gene were identified in the group of nine female patients with SBH (out of 31 patients with DCX-suggestive brain anomalies), ie 33%. We estimate an overall mutation detection rate of approximately 85% by LIS1 and DCX sequencing and MLPA in ILS, and 90% by DCX sequencing and MLPA in SBH. Our results show that intragenic deletions and duplications of the LIS1 and DCX genes account for a significant number of patients with ILS and SBH, where no molecular defect had previously been identified. Incorporation of deletion/duplication analysis of the LIS1 and DCX genes will be important for the molecular diagnosis of patients with ILS and SBH.

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

Cited by 158 publications

References 17 publications

Doublecortin Is Required in Mice for Lamination of the Hippocampus But Not the Neocortex

Doublecortin Is Required in Mice for Lamination of the Hippocampus But Not the Neocortex

Mutation analysis of the DCX gene and genotype/phenotype correlation in subcortical band heterotopia

Intragenic deletions and duplications of the LIS1 and DCX genes: a major disease-causing mechanism in lissencephaly and subcortical band heterotopia

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