人类巨脑畸形和节段性大脑过度生长-猫眼课题宝

人类巨脑畸形和节段性大脑过度生长

批准号：

8941302

负责人：

William B. Dobyns

金额：

$68.02万

依托单位：

SEATTLE CHILDREN'S HOSPITAL

依托单位国家：

美国

项目类别：

财政年份：

2015

资助国家：

美国

项目状态：

已结题

起止时间：

2015-09-30 至 2020-07-31

来源：

https://reporter.nih.gov/project-details/8941302

关键词：

AKT Signaling Pathway AKT3 gene Accounting Address Affect Antibodies Autistic Disorder Bilateral Biology Birth Brain CCND2 gene Candidate Disease Gene Cells Cerebral cortex Child Childhood Clinical Common Data Element Congenital Abnormality Cortical Dysplasia Cortical Malformation DNA Data Data Analyses Development Disease Drug Targeting Dysplasia EZH2 gene Electroencephalography Enrollment Epilepsy Future Genes Genetic Genetic study Genomics Genotype Goals Hand Head Health Histopathology Human Hydrocephalus Image Immunohistochemistry Individual Intellectual functioning disability Knowledge Lead Link Malignant Neoplasms Megalencephaly Methods Molecular Mosaicism Mutant Strains Mice Mutation Natural History Nature Outcome Measure PIK3CA gene PTEN gene Pathway interactions Pharmaceutical Preparations Pharmacotherapy Phase Phenotype Protein Array Proteomics Proto-Oncogene Proteins c-akt Reading Risk Factors Role Sampling Seizures Sequence Analysis Severity of illness Signal Pathway Signaling Molecule Skin Source Specimen Syndrome Technology Testing Therapeutic Trials Tissue Sample Tissues Validation Variant Weight Work cohort deep sequencing developmental disease effective therapy exome functional status gene discovery genome sequencing laser capture microdissection malformation mutant public health relevance targeted sequencing

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DESCRIPTION (provided by applicant): Megalencephaly (MEG) or "large brain" is a developmental disorder associated with brain overgrowth, frequent cortical malformations, and variable intellectual disability, autism, epilepsy, hydrocephalus, Chiari malformation, and a host of other developmental and health problems. MEG has historically been considered as distinct from hemimegalencephaly and focal cortical dysplasia (FCD). However, recent genetic studies have identified mutations of the same genes that all function in the PI3K-AKT intracellular signaling pathway, especially PIK3CA, PIK3R2, PTEN, AKT3 and CCND2. We have enrolled a cohort of more than 400 children with MEG-HEG-FCD syndromes, with mutations of these 5 genes found in 10% to 75% depending on the specific syndrome. In this project, we propose to better define the phenotype, perform detailed genotype-phenotype analysis, examine the PI3K-AKT and other signaling pathways by immunohistochemistry and reverse phase protein arrays, perform deep targeted sequencing for both known and strong candidate genes, study the effects of mosaicism, and search for additional causative genes using whole exome and whole genome sequencing.

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