1. The location of DCX mutations predicts malformation severity in X-linked lissencephaly
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Perrine Plouin, Pierre-Louis Leger, Hilde Van Esch, Marie Laure Moutard, Fiona Francis, Cherif Beldjord, N Bahi-Buisson, Jean Marc Pinard, Jamel Chelly, Jean Louis Renard, Isabelle Souville, Caroline Elie, Vincent des Portes, Sylvie Joriot, Nathalie Boddaert, Physiopathologie, conséquences fonctionnelles et neuroprotection des atteintes du cerveau en développement, Université Paris Diderot - Paris 7 ( UPD7 ) -IFR2-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service de Réanimation Néonatale et Pédiatrique, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Trousseau [APHP], Service de biochimie et de génétique moléculaire [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Cochin [AP-HP], Service d'informatique médicale et biostatistiques [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Service de neurologie pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP)-AP-HP Hôpital Raymond Poincaré [Garches], Etude des Civilisations de l'Antiquité ( UMR 7044 ), Université de Haute-Alsace (UHA) Mulhouse - Colmar ( Université de Haute-Alsace (UHA) ) -Université Marc Bloch - Strasbourg II-Centre National de la Recherche Scientifique ( CNRS ), Centre de Référence Maladies Rares ' malformations et maladies congénitales du cervelet ', Hospices Civils de Lyon ( HCL ) -CHU Trousseau [APHP]-Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Service de Neuropédiatrie, Université de Lyon-CHU de Lyon, Centre for Human Genetics, Katholieke Universiteit Leuven ( KU Leuven ) -University Hospitals Leuven [Leuven], Service de Neuro-pédiatrie[Lille], Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut Cochin ( UMR_S567 / UMR 8104 ), Laboratoire de biochimie et génétique moléculaire, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Cochin [AP-HP]-Université Paris Descartes - Paris 5 ( UPD5 ), CHU Necker - Enfants Malades [AP-HP], Université Paris Diderot - Paris 7 (UPD7)-IFR2-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP Hôpital Raymond Poincaré [Garches], Etude des Civilisations de l'Antiquité (UMR 7044), Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Université Marc Bloch - Strasbourg II-Centre National de la Recherche Scientifique (CNRS), Hospices Civils de Lyon (HCL)-CHU Trousseau [APHP]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven)-University Hospitals Leuven [Leuven], Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (UMR_S567 / UMR 8104), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP]-Université Paris Descartes - Paris 5 (UPD5), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Raymond Poincaré [AP-HP], Centre National de la Recherche Scientifique (CNRS)-Université Marc Bloch - Strasbourg II-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA)), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)
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Adult ,Doublecortin Domain Proteins ,Male ,Doublecortin Protein ,Adolescent ,Genotype ,DNA Mutational Analysis ,Mutation, Missense ,Lissencephaly ,Classical Lissencephalies and Subcortical Band Heterotopias ,Biology ,medicine.disease_cause ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,[SCCO]Cognitive science ,0302 clinical medicine ,Genetics ,medicine ,Missense mutation ,Humans ,Child ,Genetics (clinical) ,X chromosome ,030304 developmental biology ,0303 health sciences ,Mutation ,Pachygyria ,Neuropeptides ,Brain ,Infant ,medicine.disease ,Phenotype ,Magnetic Resonance Imaging ,Doublecortin ,Child, Preschool ,biology.protein ,[ SCCO ] Cognitive science ,Microtubule-Associated Proteins ,030217 neurology & neurosurgery - Abstract
International audience; 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.
- Published
- 2008
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