Association of MTOR Mutations With Developmental Brain Disorders, Including Megalencephaly, Focal Cortical Dysplasia, and Pigmentary Mosaicism
| Autor: | Carleton Goold, Nadia Solovieff, William B. Dobyns, Richard A. Gibbs, Elisa Rahikkala, Jonathan D. Biag, Colleen F. Macmurdo, Eric Boerwinkle, Sonya A. Gunter, Sandra L. Poliachik, Brian H.Y. Chung, Christine D. Wilson, Evan A. Boyle, Scott Mahan, Robert F. Hevner, Russell P. Saneto, Katta M. Girisha, Rebecca Leary, Wendy Winckler, Molly Weaver, Sharon S. McDaniel, Jay Shendure, Laura A. Jansen, Shanming Liu, Shalini N. Jhangiani, Andrew E. Timms, William R. Sellers, Gisele Ishak, Michael Morrissey, Michael O. Dorschner, Donna M. Muzny, Catarina D. Campbell, Jeffrey G. Ojemann, Beth Martin, Edward J. Novotny, Renzo Guerrini, Ghayda M. Mirzaa, Leon Murphy, Valerio Conti, Jonathan A. Bernstein, James R. Lupski, Sarah Collins, Suchithra Menon, Carissa Olds, Kit San Yeung |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Adult Male Hemimegalencephaly Pathology medicine.medical_specialty Adolescent Developmental Disabilities Neurogenetics Nerve Tissue Proteins Biology Mechanistic Target of Rapamycin Complex 1 medicine.disease_cause 03 medical and health sciences Epilepsy Young Adult 0302 clinical medicine medicine Animals Humans Megalencephaly Amino Acids Child Exome sequencing Cells Cultured Genetic Association Studies Retrospective Studies Cerebral Cortex Neurons Mutation Mosaicism TOR Serine-Threonine Kinases Macrocephaly Cortical dysplasia medicine.disease Embryo Mammalian Rats Malformations of Cortical Development 030104 developmental biology Gene Expression Regulation Child Preschool Multiprotein Complexes Intercellular Signaling Peptides and Proteins Female Neurology (clinical) medicine.symptom 030217 neurology & neurosurgery |
| Zdroj: | JAMA neurology. 73(7) |
| ISSN: | 2168-6157 |
| Popis: | Importance Focal cortical dysplasia (FCD), hemimegalencephaly, and megalencephaly constitute a spectrum of malformations of cortical development with shared neuropathologic features. These disorders are associated with significant childhood morbidity and mortality. Objective To identify the underlying molecular cause of FCD, hemimegalencephaly, and diffuse megalencephaly. Design, Setting, and Participants Patients with FCD, hemimegalencephaly, or megalencephaly (mean age, 11.7 years; range, 2-32 years) were recruited from Pediatric Hospital A. Meyer, the University of Hong Kong, and Seattle Children’s Research Institute from June 2012 to June 2014. Whole-exome sequencing (WES) was performed on 8 children with FCD or hemimegalencephaly using standard-depth (50-60X) sequencing in peripheral samples (blood, saliva, or skin) from the affected child and their parents and deep (150-180X) sequencing in affected brain tissue. Targeted sequencing and WES were used to screen 93 children with molecularly unexplained diffuse or focal brain overgrowth. Histopathologic and functional assays of phosphatidylinositol 3-kinase–AKT (serine/threonine kinase)–mammalian target of rapamycin (mTOR) pathway activity in resected brain tissue and cultured neurons were performed to validate mutations. Main Outcomes and Measures Whole-exome sequencing and targeted sequencing identified variants associated with this spectrum of developmental brain disorders. Results Low-level mosaic mutations ofMTORwere identified in brain tissue in 4 children with FCD type 2a with alternative allele fractions ranging from 0.012 to 0.086. Intermediate-level mosaic mutation ofMTOR(p.Thr1977Ile) was also identified in 3 unrelated children with diffuse megalencephaly and pigmentary mosaicism in skin. Finally, a constitutional de novo mutation ofMTOR(p.Glu1799Lys) was identified in 3 unrelated children with diffuse megalencephaly and intellectual disability. Molecular and functional analysis in 2 children with FCD2a from whom multiple affected brain tissue samples were available revealed a mutation gradient with an epicenter in the most epileptogenic area. When expressed in cultured neurons, allMTORmutations identified here drive constitutive activation of mTOR complex 1 and enlarged neuronal size. Conclusions and Relevance In this study, mutations ofMTORwere associated with a spectrum of brain overgrowth phenotypes extending from FCD type 2a to diffuse megalencephaly, distinguished by different mutations and levels of mosaicism. These mutations may be sufficient to cause cellular hypertrophy in cultured neurons and may provide a demonstration of the pattern of mosaicism in brain and substantiate the link between mosaic mutations ofMTORand pigmentary mosaicism in skin. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|