title: From Function to Phenotype: Impaired DNA Binding and Clustering Correlates with Clinical Severity in Males with Missense Mutations in MECP2.
abstract: Mutations in the MECP2 gene cause Rett syndrome (RTT). MeCP2 binds to chromocentric DNA through its methyl CpG-binding domain (MBD) to regulate gene expression. In heterozygous females the variable phenotypic severity is modulated by non-random X-inactivation, thus making genotype-phenotype comparisons unreliable. However, genotype-phenotype correlations in males with hemizygousMECP2 mutations can provide more accurate insights in to the true biological effect of specific mutations. Here, we compared chromatin organization and binding dynamics for twelve MeCP2 missense mutations (including two novel and the five most common MBD missense RTT mutations) and identifiedacorrelation with phenotype in hemizygous males. We observed impaired interaction of MeCP2-DNA for mutations around the MBD-DNA binding interface, and defective chromatin clustering for distal MBD mutations. Furthermore, binding and mobility dynamics show a gradient of impairment depending on the amino acid properties and tertiary structure within the MBD. Interestingly, a wide range of phenotypic/clinical severity, ranging from neonatal encephalopathy to mild psychiatric abnormalities were observed and all are consistent with our functional/molecular results. Overall, clinical severity showed a direct correlation with the functional impairment of MeCP2. These mechanistic and phenotypic correlations of MeCP2 mutations will enable improved and individualized diagnostics, and may lead to personalized therapeutic interventions.
authors.affiliation: Molecular Neuropsychiatry &Development (MiND) Lab, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.|Institute of Medical Science, University of Toronto, Toronto, ON, Canada.
authors.forename: Taimoor I
authors.initials: TI
authors.lastname: Sheikh
authors.affiliation: Department of Biochemistry and Microbiology, University of Victoria, BC, Canada.
authors.forename: Juan
authors.initials: J
authors.lastname: Ausió
authors.affiliation: The Fred A. Litwin Family Centre in Genetic Medicine, University Health Network and Mount Sinai Hospital, Toronto, ON, Canada.
authors.forename: Hannah
authors.initials: H
authors.lastname: Faghfoury
authors.affiliation: The Fred A. Litwin Family Centre in Genetic Medicine, University Health Network and Mount Sinai Hospital, Toronto, ON, Canada.
authors.forename: Josh
authors.initials: J
authors.lastname: Silver
authors.affiliation: Civitan International Research Center, University of Alabama at Birmingham, AL, USA.
authors.forename: Jane B
authors.initials: JB
authors.lastname: Lane
authors.affiliation: Division of Genetics and Development, Toronto Western Research Institute, University Health Network, Toronto, ON, Canada.|Department of Physiology, University of Toronto, Toronto, ON, Canada.|Department of Surgery (Neurosurgery), University of Toronto, Toronto, ON, Canada.
authors.forename: James H
authors.initials: JH
authors.lastname: Eubanks
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Patrick
authors.initials: P
authors.lastname: MacLeod
authors.affiliation: Civitan International Research Center, University of Alabama at Birmingham, AL, USA.
authors.forename: Alan K
authors.initials: AK
authors.lastname: Percy
authors.affiliation: Molecular Neuropsychiatry &Development (MiND) Lab, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.|Institute of Medical Science, University of Toronto, Toronto, ON, Canada.|Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
authors.forename: John B
authors.initials: JB
authors.lastname: Vincent
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D020125:Mutation, Missense; D032446:Myoblasts; D009690:Nucleic Acid Conformation; D010641:Phenotype; D011485:Protein Binding; D011487:Protein Conformation; D015518:Rett Syndrome / Q000175:diagnosis* / Q000235:genetics*; D012720:Severity of Illness Index
chemical_list: C497392:MECP2 protein, human; D051783:Methyl-CpG-Binding Protein 2; D004247:DNA