title: Recurrent KIF2A mutations are responsible for classic lissencephaly.
abstract: Kinesins play a critical role in the organization and dynamics of the microtubule cytoskeleton, making them central players in neuronal proliferation, neuronal migration, and postmigrational development. Recently, KIF2A mutations were identified in cortical malformation syndromes associated with microcephaly. Here, we detected two de novo p.Ser317Asn and p.His321Pro mutations in KIF2A in two patients with lissencephaly and microcephaly. In parallel, we re-evaluated the two previously reported cases showing de novo mutations of the same residues. The identification of mutations only in the residues Ser317 and His321 suggests these are hotspots for de novo mutations. Both mutations lead to a classic form of lissencephaly, with a posterior to anterior gradient, almost indistinguishable from LIS1-related lissencephaly. However, three fourths of patients also showed variable congenital and postnatal microcephaly, up to -5 SD. Located in the motor domain of the KIF2A protein, the Ser317 and His321 alterations are expected to disrupt binding or hydrolysis of ATP and consequently the MT depolymerizing activity. This report also establishes that KIF2A mutations represent significant causes of classic lissencephaly with microcephaly.
authors.affiliation: Imagine Institute, Paris Descartes-Sorbonne Paris Cité University, Paris, France.|INSERM UMR-1163, Embryology and Genetics of Congenital Malformations, Paris, France.
authors.forename: Mara
authors.initials: M
authors.lastname: Cavallin
authors.affiliation: Department of Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Emilia K
authors.initials: EK
authors.lastname: Bijlsma
authors.affiliation: INSERM UMR-1163, Genetics of Mitochondrial Diseases, Genetics Department, Necker Enfants Malades Hospital, Paris, France.|INSERM UMR-1163, Laboratory of Neurogenetics, Paris, France.
authors.forename: Adrienne
authors.initials: A
authors.lastname: El Morjani
authors.affiliation: Service de Génétique Médicale, Centre de Référence des Anomalies du Développement Embryonnaire, CHU Bordeaux, Hôpital Pellegrin, Bordeaux, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Moutton
authors.affiliation: Department of Pediatric Neurology, Juliana Children's Hospital/HAGA Teaching Hospital, The Hague, The Netherlands.
authors.forename: Els A J
authors.initials: EA
authors.lastname: Peeters
authors.affiliation: Imagine Institute, Paris Descartes-Sorbonne Paris Cité University, Paris, France.|INSERM UMR-1163, Embryology and Genetics of Congenital Malformations, Paris, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Maillard
authors.affiliation: Service de Neurologie Pédiatrique, CHU Bordeaux, Hôpital Pellegrin, Bordeaux, France.
authors.forename: Jean Michel
authors.initials: JM
authors.lastname: Pedespan
authors.affiliation: Service de Génétique, CHU de Rouen et Inserm U1079, Centre Normand de Génomique Médicale et Médecine Personnalisée, Université de Rouen, Rouen, France.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Guerrot
authors.affiliation: Service de Génétique, CHU de Rouen et Inserm U1079, Centre Normand de Génomique Médicale et Médecine Personnalisée, Université de Rouen, Rouen, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Drouin-Garaud
authors.affiliation: Département de Génétique Médicale, Maladies Rares et Médecine Personnalisée, Unité Inserm U1183, CHU Montpellier, Université Montpellier, Montpellier, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Coubes
authors.affiliation: Département de Génétique Médicale, Maladies Rares et Médecine Personnalisée, Unité Inserm U1183, CHU Montpellier, Université Montpellier, Montpellier, France.
authors.forename: David
authors.initials: D
authors.lastname: Genevieve
authors.affiliation: Plateforme Bioinformatique, Imagine Institute, Paris Descartes-Sorbonne Paris Cité University, Paris, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Bole-Feysot
authors.affiliation: Plateforme Bioinformatique, Imagine Institute, Paris Descartes-Sorbonne Paris Cité University, Paris, France.
authors.forename: Cecile
authors.initials: C
authors.lastname: Fourrage
authors.affiliation: Imagine Institute, Paris Descartes-Sorbonne Paris Cité University, Paris, France.|INSERM UMR-1163, Genetics of Mitochondrial Diseases, Genetics Department, Necker Enfants Malades Hospital, Paris, France.|INSERM UMR-1163, Laboratory of Neurogenetics, Paris, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Steffann
authors.affiliation: Imagine Institute, Paris Descartes-Sorbonne Paris Cité University, Paris, France. nadia.bahi-buisson@nck.aphp.fr.|INSERM UMR-1163, Embryology and Genetics of Congenital Malformations, Paris, France. nadia.bahi-buisson@nck.aphp.fr.|Plateforme Bioinformatique, Imagine Institute, Paris Descartes-Sorbonne Paris Cité University, Paris, France. nadia.bahi-buisson@nck.aphp.fr.|Pediatric Neurology, Necker Enfants Malades University Hospital, APHP, Paris, France. nadia.bahi-buisson@nck.aphp.fr.|Institut Imagine-INSERM UMR-1163, Embryology and Genetics of Congenital Malformations, Université Paris Descartes-Sorbonne Paris Cité, Paris, France. nadia.bahi-buisson@nck.aphp.fr.
authors.forename: Nadia
authors.initials: N
authors.lastname: Bahi-Buisson
mesh_terms: D000293:Adolescent; D054221:Classical Lissencephalies and Subcortical Band Heterotopias / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency; D006801:Humans; D007223:Infant; D016547:Kinesins / Q000235:genetics*; D054082:Lissencephaly / Q000235:genetics; D008297:Male; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide
chemical_list: C509805:KIF2A protein, human; D016547:Kinesins
keywords: KIF2A; Kinesin; Lissencephaly