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

中文摘要

翻译

描述（由申请人提供）：巨脑畸形（MEG）或"大脑"是一种发育障碍，与脑过度生长、频繁皮质畸形和各种智力残疾、自闭症、癫痫、脑积水、基亚里畸形以及许多其他发育和健康问题相关。MEG在历史上被认为与半侧巨脑畸形和局灶性皮质发育不良（FCD）不同。然而，最近的遗传学研究已经鉴定了在PI3K-AKT细胞内信号传导途径中都起作用的相同基因的突变，特别是PIK3CA、PIK3R2、PTEN、AKT3和CCND2。我们招募了400多名患有MEG-HEG-FCD综合征的儿童，根据具体的综合征，这5种基因的突变率为10%至75%。在这个项目中，我们建议更好地定义表型，进行详细的基因型-表型分析，通过免疫组织化学和反相蛋白阵列检查PI3K-AKT和其他信号通路，对已知和强候选基因进行深度靶向测序，研究嵌合现象的影响，并使用全外显子组和全基因组测序寻找其他致病基因。

英文摘要

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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