title: The location of DCX mutations predicts malformation severity in X-linked lissencephaly.
abstract: Lissencephaly spectrum (LIS) is one of the most severe neuronal migration disorders that ranges from agyria/pachygyria to subcortical band heterotopia. Approximately 80% of patients with the LIS spectrum carry mutations in either the LIS1 or DCX (doublecortin) genes which have an opposite gradient of severity. The aim of the study was to evaluate in detail the phenotype of DCX-associated lissencephaly and to look for genotype-phenotype correlations. Of the 180 male patients with DCX-related lissencephaly, 33 males (24 familial cases and nine cases with de novo mutations) were found with hemizygous DCX mutations and were clinically and genetically assessed here. DCX mutation analysis revealed that the majority of mutations were missense (79.2%), clustered in the two evolutionary conserved domains, N-DC and C-DC, of DCX. The most prominent radiological phenotype was an anteriorly predominant pachygyria or agyria (54.5%) although DCX-associated lissencephaly encompasses a complete range of LIS grades. The severity of neurological impairment was in accordance with the degree of agyria with severe cognitive impairment in all patients, inability to walk independently in over half and refractory epilepsy in more than a third. For genotype-phenotype correlations, patients were divided in two groups according to the location of DCX missense mutations. Patients with mutations in the C-DC domain tended to have a less severe lissencephaly (grade 4-5 in 58.3%) compared with those in the N-DC domain (grade 4-5 in 36.3%) although, in this dataset, this was not statistically significant (p = 0.12). Our evaluation suggests a putative correlation between phenotype and genotype. These data provide further clues to deepen our understanding of the function of the DCX protein and may give new insights into the molecular mechanisms that could influence the consequence of the mutation in the N-DC versus the C-DC domain of DCX.
authors.affiliation: Département de Pédiatrie, Hopital Necker Enfants Malades, AP-HP, Université Paris Descartes, Paris, France.
authors.forename: Pierre-Louis
authors.initials: PL
authors.lastname: Leger
authors.forename: Isabelle
authors.initials: I
authors.lastname: Souville
authors.forename: Nathalie
authors.initials: N
authors.lastname: Boddaert
authors.forename: Caroline
authors.initials: C
authors.lastname: Elie
authors.forename: Jean Marc
authors.initials: JM
authors.lastname: Pinard
authors.forename: Perrine
authors.initials: P
authors.lastname: Plouin
authors.forename: Marie Laure
authors.initials: ML
authors.lastname: Moutard
authors.forename: Vincent
authors.initials: V
authors.lastname: des Portes
authors.forename: Hilde
authors.initials: H
authors.lastname: Van Esch
authors.forename: Sylvie
authors.initials: S
authors.lastname: Joriot
authors.forename: Jean Louis
authors.initials: JL
authors.lastname: Renard
authors.forename: Jamel
authors.initials: J
authors.lastname: Chelly
authors.forename: Fiona
authors.initials: F
authors.lastname: Francis
authors.forename: Cherif
authors.initials: C
authors.lastname: Beldjord
authors.forename: Nadia
authors.initials: N
authors.lastname: Bahi-Buisson
mesh_terms: D000293:Adolescent; D000328:Adult; D001921:Brain / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D054221:Classical Lissencephalies and Subcortical Band Heterotopias / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology / Q000523:psychology; D004252:DNA Mutational Analysis; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D005838:Genotype; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging; D008297:Male; D008869:Microtubule-Associated Proteins / Q000737:chemistry / Q000235:genetics*; D009154:Mutation; D020125:Mutation, Missense; D009479:Neuropeptides / Q000737:chemistry / Q000235:genetics*; D010641:Phenotype
chemical_list: C000714328:DCX protein, human; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides