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

Matsumoto, Naomichi; Leventer, Richard J.; Kuc, Julie A.; Mewborn, Stephanie K.; Dudlicek, L.; Ramocki, Melissa B.; Pilz, Daniela T.; Mills, Patti L.; Das, Soma; Ross, M. Elizabeth; Ledbetter, David H.; Dobyns, William B.

doi:10.1038/sj.ejhg.5200548

Cited by 144 publications

(112 citation statements)

References 23 publications

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“…Mutations of the DCX gene are present in approximately 85% of SBH patients 24 and we have found intragenic deletions of the DCX gene in an additional 4% (27% of patients without DCX mutations). Our results are similar to Mei et al (2007) who described the presence of DCX intragenic deletions in 27% of their SBH patients in whom no DCX mutations had been identified by sequencing.…”

Section: Discussionmentioning

confidence: 63%

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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Section: Discussionmentioning

confidence: 63%

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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“…The LIS1 gene causes the autosomal form of LIS [Reiner et al, 1993], while the DCX gene is X linked [des Portes et al, 1998;Gleeson et al, 1998]. Although each gene can result in either LIS or SBH, most cases of classic LIS are due to deletions or mutations in the LIS1 gene [Mei et al, 2008], whereas most cases of SBH are due to mutations in the DCX gene [Matsumoto et al, 2001]. LIS1 encodes a 45-kDa protein (PAFAH1B1), which functions as a regulatory subunit of platelet-activating factor acetylhydrolase (PAF-AH) [Hirotsune et al, 1998].…”

Section: Clinical Featuresmentioning

confidence: 99%

Genetic Basis of Brain Malformations

et al. 2016

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Malformations of cortical development (MCD) represent a major cause of developmental disabilities, severe epilepsy, and reproductive disadvantage. Genes that have been associated to MCD are mainly involved in cell proliferation and specification, neuronal migration, and late cortical organization. Lissencephaly-pachygyria-severe band heterotopia are diffuse neuronal migration disorders causing severe global neurological impairment. Abnormalities of the LIS1, DCX, ARX, RELN, VLDLR, ACTB, ACTG1, TUBG1, KIF5C, KIF2A, and CDK5 genes have been associated with these malformations. More recent studies have also established a relationship between lissencephaly, with or without associated microcephaly, corpus callosum dysgenesis as well as cerebellar hypoplasia, and at times, a morphological pattern consistent with polymicrogyria with mutations of several genes (TUBA1A, TUBA8, TUBB, TUBB2B, TUBB3, and DYNC1H1), regulating the synthesis and function of microtubule and centrosome key components and hence defined as tubulinopathies. MCD only affecting subsets of neurons, such as mild subcortical band heterotopia and periventricular heterotopia, have been associated with abnormalities of the DCX, FLN1A, and ARFGEF2 genes and cause neurological and cognitive impairment that vary from severe to mild deficits. Polymicrogyria results from abnormal late cortical organization and is inconstantly associated with abnormal neuronal migration. Localized polymicrogyria has been associated with anatomo-specific deficits, including disorders of language and higher cognition. Polymicrogyria is genetically heterogeneous, and only in a small minority of patients, a definite genetic cause has been identified. Megalencephaly with normal cortex or polymicrogyria by MRI imaging, hemimegalencephaly and focal cortical dysplasia can all result from mutations in genes of the PI3K-AKT-mTOR pathway. Postzygotic mutations have been described for most MCD and can be limited to the dysplastic tissue in the less diffuse forms.

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“…Mutations in DCX have been found in families, with females presenting SBH and males presenting LIS. Also 80-90% of sporadic DCX mutations are found in females, versus 25% in males with SBH [31,99]. De novo mutations show a higher proportion of nonsense and frameshift changes, and are likely therefore to lead to a more severely perturbed protein [98].…”

Section: 212a Doublecortin (Dcx)mentioning

confidence: 99%