Megalencephaly and segmental brain overgrowth in humans

人类巨脑畸形和节段性大脑过度生长

• 批准号: 9751409
• 负责人: Kathleen Joyce Millen
• 金额: $ 66.62万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9751409
• 关键词: AKT Signaling Pathway; AKT3 gene; Address; Affect; Antibodies; Bilateral; Biology; Birth; Brain; Brain imaging; CCND2 gene; Candidate Disease Gene; Cells; Cerebral cortex; Child; Clinical; Common Data Element; Congenital Abnormality; Cortical Dysplasia; Cortical Malformation; DNA; Data; Development; Disease; Drug Targeting; Dysplasia; EZH2 gene; Electroencephalography; Enrollment; Epilepsy; Future; Genes; Genetic; Genetic study; Genomics; Genotype; Goals; Hand; Head; Health; Histopathology; Human; Hydrocephalus; 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; Pathologic; Pathway interactions; Pharmaceutical Preparations; Phase; Phenotype; Protein Array; Proteomics; Proto-Oncogene Proteins c-akt; Risk Factors; Role; Sampling; Seizures; Severity of illness; Signal Pathway; Signaling Molecule; Skin; Source; Specimen; Syndrome; Technology; Testing; Therapeutic Trials; Tissue Sample; Tissues; Validation; Variant; Weight; Work; autism spectrum disorder; brain overgrowth; brain size; brain tissue; childhood epilepsy; cohort; deep sequencing; developmental disease; effective therapy; exome; functional status; gene discovery; genome sequencing; hemimegalencephaly; laser capture microdissection; malformation; mutant; mutational status; phenotypic data; public health relevance; targeted sequencing; targeted treatment; whole genome

 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.

 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PI 3 K-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PIK 3CA、PIK 3R 2、PTEN、AKT 3和CCND 2。 我们招募了400多名患有MEG-HEG-FCD综合征的儿童，根据具体综合征，这5个基因的突变率为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PI 3 K-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。

项目成果

Human mutations in integrator complex subunits link transcriptome integrity to brain development.

• DOI: 10.1371/journal.pgen.1006809
• 发表时间: 2017-05
• 期刊: PLoS genetics
• 影响因子: 4.5
• 作者: Oegema R;Baillat D;Schot R;van Unen LM;Brooks A;Kia SK;Hoogeboom AJM;Xia Z;Li W;Cesaroni M;Lequin MH;van Slegtenhorst M;Dobyns WB;de Coo IFM;Verheijen FW;Kremer A;van der Spek PJ;Heijsman D;Wagner EJ;Fornerod M;Mancini GMS
• 通讯作者: Mancini GMS

Weaver Syndrome-Associated EZH2 Protein Variants Show Impaired Histone Methyltransferase Function In Vitro.

• DOI: 10.1002/humu.22946
• 发表时间: 2016-03
• 期刊: Human mutation
• 影响因子: 3.9
• 作者: Cohen AS;Yap DB;Lewis ME;Chijiwa C;Ramos-Arroyo MA;Tkachenko N;Milano V;Fradin M;McKinnon ML;Townsend KN;Xu J;Van Allen MI;Ross CJ;Dobyns WB;Weaver DD;Gibson WT
• 通讯作者: Gibson WT