title: A nonsense variant in HERC1 is associated with intellectual disability, megalencephaly, thick corpus callosum and cerebellar atrophy.
abstract: Megalencephaly is a congenital condition characterized by severe overdeveloped brain size. This phenotype is often caused by mutations affecting the RTK/PI3K/mTOR (receptor tyrosine kinase-phosphatidylinositol-3-kinase-AKT) signaling and its downstream pathway of mammalian target of rapamycin (mTOR). Here, using a whole-exome sequencing in a Moroccan consanguineous family, we show that a novel autosomal-recessive neurological condition characterized by megalencephaly, thick corpus callosum and severe intellectual disability is caused by a homozygous nonsense variant in the HERC1 gene. Assessment of the primary skin fibroblast from the proband revealed complete absence of the HERC1 protein. HERC1 is an ubiquitin ligase that interacts with tuberous sclerosis complex 2, an upstream negative regulator of the mTOR pathway. Our data further emphasize the role of the mTOR pathway in the regulation of brain development and the power of next-generation sequencing technique in elucidating the genetic etiology of autosomal-recessive disorders and suggest that HERC1 defect might be a novel cause of autosomal-recessive syndromic megalencephaly.
authors.affiliation: Laboratory of Molecular and Pathophysiological Bases of Cognitive Disorders, INSERM UMR 1163, Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, Necker-Enfants Malades Hospital, Paris, France.
authors.forename: Lam Son
authors.initials: LS
authors.lastname: Nguyen
authors.affiliation: Departament de Ciències Fisiològiques II, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Universitat de Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Taiane
authors.initials: T
authors.lastname: Schneider
authors.affiliation: Laboratory of Molecular and Pathophysiological Bases of Cognitive Disorders, INSERM UMR 1163, Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, Necker-Enfants Malades Hospital, Paris, France.
authors.forename: Marlène
authors.initials: M
authors.lastname: Rio
authors.affiliation: Laboratory of Molecular and Pathophysiological Bases of Cognitive Disorders, INSERM UMR 1163, Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, Necker-Enfants Malades Hospital, Paris, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Moutton
authors.affiliation: Laboratory of Molecular and Pathophysiological Bases of Cognitive Disorders, INSERM UMR 1163, Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, Necker-Enfants Malades Hospital, Paris, France.
authors.forename: Karine
authors.initials: K
authors.lastname: Siquier-Pernet
authors.affiliation: Laboratory of Molecular and Pathophysiological Bases of Cognitive Disorders, INSERM UMR 1163, Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, Necker-Enfants Malades Hospital, Paris, France.
authors.forename: Florine
authors.initials: F
authors.lastname: Verny
authors.affiliation: Laboratory of Molecular and Pathophysiological Bases of Cognitive Disorders, INSERM UMR 1163, Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, Necker-Enfants Malades Hospital, Paris, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Boddaert
authors.affiliation: Laboratory of Molecular and Pathophysiological Bases of Cognitive Disorders, INSERM UMR 1163, Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, Necker-Enfants Malades Hospital, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Desguerre
authors.affiliation: Laboratory of Molecular and Pathophysiological Bases of Cognitive Disorders, INSERM UMR 1163, Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, Necker-Enfants Malades Hospital, Paris, France.
authors.forename: Arnold
authors.initials: A
authors.lastname: Munich
authors.affiliation: Departament de Ciències Fisiològiques II, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Universitat de Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: José Luis
authors.initials: JL
authors.lastname: Rosa
authors.affiliation: Laboratory of Molecular and Pathophysiological Bases of Cognitive Disorders, INSERM UMR 1163, Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, Necker-Enfants Malades Hospital, Paris, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Cormier-Daire
authors.affiliation: Laboratory of Molecular and Pathophysiological Bases of Cognitive Disorders, INSERM UMR 1163, Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, Necker-Enfants Malades Hospital, Paris, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Colleaux
mesh_terms: D000293:Adolescent; D001284:Atrophy; D001483:Base Sequence; D002531:Cerebellum / Q000473:pathology*; D002648:Child; D002675:Child, Preschool; D018389:Codon, Nonsense / Q000235:genetics*; D003337:Corpus Callosum / Q000473:pathology*; D005260:Female; D020022:Genetic Predisposition to Disease; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics*; D006801:Humans; D007231:Infant, Newborn; D008607:Intellectual Disability / Q000150:complications / Q000235:genetics*; D008297:Male; D058627:Megalencephaly / Q000150:complications / Q000235:genetics*; D008969:Molecular Sequence Data; D010375:Pedigree; D044767:Ubiquitin-Protein Ligases
chemical_list: D018389:Codon, Nonsense; D020662:Guanine Nucleotide Exchange Factors; C102169:HERC1 protein, human; D044767:Ubiquitin-Protein Ligases