The location of DCX mutations predicts malformation severity in X-linked lissencephaly.
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.
Leger
Pierre-Louis
PL
Département de Pédiatrie, Hopital Necker Enfants Malades, AP-HP, Université Paris Descartes, Paris, France.
Souville
Isabelle
I
Boddaert
Nathalie
N
Elie
Caroline
C
Pinard
Jean Marc
JM
Plouin
Perrine
P
Moutard
Marie Laure
ML
des Portes
Vincent
V
Van Esch
Hilde
H
Joriot
Sylvie
S
Renard
Jean Louis
JL
Chelly
Jamel
J
Francis
Fiona
F
Beldjord
Cherif
C
Bahi-Buisson
Nadia
N
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
C000714328:DCX protein, human; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides