A nonsense variant in HERC1 is associated with intellectual disability, megalencephaly, thick corpus callosum and cerebellar atrophy

• Published in: European journal of human genetics : EJHG Vol. 24; no. 3; pp. 455 - 458
• Main Authors: Nguyen, Lam Son, Schneider, Taiane, Rio, Marlène, Moutton, Sébastien, Siquier-Pernet, Karine, Verny, Florine, Boddaert, Nathalie, Desguerre, Isabelle, Munich, Arnold, Rosa, José Luis, Cormier-Daire, Valérie, Colleaux, Laurence
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01-03-2016
• Subjects: 1-Phosphatidylinositol 3-kinase; Adolescent; AKT protein; Atrophy; Base Sequence; Cerebellum; Cerebellum - pathology; Child; Child, Preschool; Codon, Nonsense - genetics; Corpus callosum; Corpus Callosum - pathology; Etiology; Female; Genetic Predisposition to Disease; Genetics; Guanine Nucleotide Exchange Factors - genetics; HERC1 gene; Human genetics; Humans; Infant, Newborn; Intellectual disabilities; Intellectual Disability - complications; Intellectual Disability - genetics; Life Sciences; Male; Megalencephaly - complications; Megalencephaly - genetics; Molecular Sequence Data; Pedigree; Phenotypes; Protein-tyrosine kinase; Protein-tyrosine kinase receptors; Rapamycin; Sclerosis; Short Report; Skin; TOR protein; Tuberous sclerosis; Tyrosine; Ubiquitin; Ubiquitin-protein ligase; France; United States > US
• ISSN: 1018-4813; 1476-5438
• DOI: 10.1038/ejhg.2015.140

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.