Megalencephaly and segmental brain overgrowth in humans

人类巨脑畸形和节段性大脑过度生长

基本信息

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
项目类别：
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

项目摘要

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.

描述（由申请人提供）：巨脑畸形（MEG）或“大脑”是一种与大脑过度生长、频繁的皮质畸形和不同程度的智力障碍、自闭症、癫痫、脑积水、Chiari 畸形以及许多其他发育和发育障碍相关的发育障碍。 MEG 历来被认为与半侧巨脑畸形和局灶性皮质发育不良 (FCD) 不同，但最近的遗传学研究发现了相同基因的突变。所有这些基因都在 PI3K-AKT 细胞内信号通路中发挥作用，特别是 PIK3CA、PIK3R2、PTEN、AKT3 和 CCND2。我们招募了 400 多名 MEG-HEG-FCD 综合征儿童，其中 10% 的儿童存在这 5 个基因的突变。到 75%，具体取决于具体的综合征。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，检查通过免疫组织化学和反相蛋白阵列检测 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，研究镶嵌现象的影响，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

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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

韦弗综合征相关的 EZH2 蛋白变体在体外显示组蛋白甲基转移酶功能受损。

DOI：
发表时间：
2016-03
期刊：
影响因子：
3.9
作者：
Cohen, Ana S A;Yap, Damian B;Lewis, M E Suzanne;Chijiwa, Chieko;Ramos;Tkachenko, Natália;Milano, Valentina;Fradin, Mélanie;McKinnon, Margaret L;Townsend, Katelin N;Xu, Jieqing;Van Allen, M I;Ross, Colin J D;Dobyns, William B
通讯作者：
Dobyns, William B

ENDOVASCULAR TREATMENT OF BRAIN ARTERIOVENOUS MALFORMATIONS USING PRECIPITATING HYDROPHOBIC INJECTABLE LIQUID (

使用沉淀疏水注射液对脑动静脉畸形进行血管内治疗（

DOI：
发表时间：
2024-09-13
期刊：
影响因子：
0
作者：
K. Orlov;N. Strelnikov;V. Berestov;M. Deb;G. Thomalla;U. Hanning;J. Fiehler;S. Gellißen
通讯作者：
S. Gellißen

A Recurrent Mosaic Mutation in SMO, Encoding the Hedgehog Signal Transducer Smoothened, Is the Major Cause of Curry-Jones Syndrome.

SMO 中的复发性马赛克突变编码刺猬信号传感器平滑，是咖喱琼斯综合症的主要原因。

DOI：
10.1016/j.ajhg.2016.04.007
发表时间：
2016-06-02
期刊：
American journal of human genetics
影响因子：
9.8
作者：
S. Twigg;R. Hufnagel;K. Miller;Yan Zhou;S. McGowan;John M. Taylor;Jude Craft;Jenny C. Taylor;S. Santoro;Taosheng Huang;R. Hopkin;A. Brady;J. Clayton;C. Clericuzio;D. Grange;L. Groesser;C. Hafner;D. Horn;I. Temple;W. Dobyns;C. Curry;Marilyn C. Jones;A. Wilkie
通讯作者：
A. Wilkie

SETD2 相关过度生长综合征：四位新患者的介绍和文献综述。

DOI：
发表时间：
2019
期刊：
影响因子：
0
作者：
Marzin, Pauline;Rondeau, Sophie;Aldinger, Kimberly A;Alessandri, Jean;Isidor, Bertrand;Heron, Delphine;Keren, Boris;Dobyns, William B;Cormier
通讯作者：
Cormier

Preoperative Facial Nerve Mapping to Plan and Guide Pediatric Facial Vascular Anomaly Resection.

术前面神经测绘，以规划和指导小儿面部血管异常切除术。

DOI：
发表时间：
2018-05-01
期刊：
影响因子：
0
作者：
Bly, Randall A;Holdefer, Robert N;Slimp, Jefferson;Kinney, Gregory A;Martinez, Vicente;Manning, Scott C;Perkins, Jonathan A
通讯作者：
Perkins, Jonathan A