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Human Genetics and Molecular Mechanisms of Vein of Galen Aneurysmal Malformation

Galen 动脉瘤畸形静脉的人类遗传学和分子机制

基本信息

批准号：
10673038
负责人：
Titus Jonathon Boggon
金额：
$ 55.3万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-15 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10673038
关键词：
ACVR1 gene ACVRL1 gene Address Antibodies Arteriovenous malformation Autopsy Biochemical Biochemistry Bioinformatics Biological Biological Assay Biophysics Biopsy Blood Vessels Blood capillaries Brain Diseases Cells Cellular biology Cerebrovascular system Childhood Clinical Complex Cutaneous DNA Resequencing DNA sequencing Data Decision Making Development Diagnostic Disease Disease Management Ephrin-B2 Ephrins FRAP1 gene Foundations Functional disorder Galen Vein Gene Mutation Genes Genetic Counseling Genetic study Genomic approach Germ-Line Mutation Heterogeneity Human Human Genetics In Vitro Inherited Intervention Intracranial Aneurysm Intracranial Hemorrhages Knowledge Lesion Ligands Mass Spectrum Analysis Measures Molecular Mosaicism Mutate Mutation Nature Neurons Ontology Parents Pathogenesis Pathway interactions Patients Phenotype Phosphotransferases Proteomics Resolution Role Scheme Signal Pathway Signal Transduction Skin Somatic Mutation Specific qualifier value Structure Syndrome Techniques Testing Therapeutic Therapeutic Intervention Tissues Validation Variant bioinformatics pipeline brain arteriovenous malformations candidate validation cerebrovascular cerebrovascular lesion cohort congenital anomaly de novo mutation deep sequencing design drug repurposing exome sequencing experience experimental study functional genomics gene discovery gene function genetic architecture genetic pedigree genome-wide improved in silico insight interdisciplinary approach interest malformation mosaic mosaic variant neurosurgery next generation novel prognostication protein complex protein structure ras GTPase-Activating Proteins recruit segregation spatiotemporal structural biology targeted treatment transmission process

项目摘要

PROJECT SUMMARY The genetic study of severe human congenital cerebrovascular anomalies can shed insight into mechanisms of normal vascular development and identify targets for therapeutic intervention. Vein of Galen aneurysmal malformations (VOGMs) are the most common and severe of pediatric brain arterio-venous malformations (AVMs). Significant gaps in our understanding of the molecular pathogenesis of VOGMs impede the development of improved diagnostic and therapeutic measures. Locus heterogeneity and the sporadic nature of VOGM cases have constituted fundamental obstacles to VOGM gene discovery. We recently applied whole exome sequencing (WES) to overcome these obstacles and identified de novo and inherited gene mutations that account for ~30% of sporadic VOGM cases (Duran et al., Neuron, 2019). These included a genome-wide significant burden of rare, damaging mutations in EPHB4 (EphB4), a critical regulator of arterio-venous specification also mutated in the familial AVM syndrome, capillary malformation (CM)-AVM type II (CM-AVM2). We also discovered new mutations in other genes that function in the same Ephrin signaling interactome, including RASA1 (also mutated in CM-AVM1). We further demonstrated that EphB4 exists in a physical complex with RASA1, and have now solved the first multi-domain crystal structure of RASA1. Nonetheless, most VOGM cases remain genetically unsolved, and the molecular mechanisms of VOGM-associated mutations are poorly understood. To address these knowledge gaps, we propose a functional genomics approach to discover and mechanistically elucidate VOGM-associated mutations with atomic-level resolution. We hypothesize WES will identify novel VOGM genes and mutations, including mosaic and somatic “second-hit” mutations, which disrupt the regulated activity of an EphB4-RASA1 signaling complex essential for arterio-venous development. Based on our successful experience in identifying structural brain disorder genes over the past several years, Aim 1 will ascertain additional VOGM case-parent trios and perform WES on our growing cohort (already the largest in the world) to discover novel de novo and transmitted germline VOGM gene mutations, mosaic variants, and somatic mutations in lesional tissue. In Aim 2, we will determine the structural and functional impact of VOGM mutations using biochemical, biophysical, structural biology and cell biology techniques, with validation experiments in autopsied VOGM tissue, and in skin biopsies of VOGM patients with associated cutaneous vascular malformations. Successful completion of these Aims will increase our understanding of human cerebrovascular development and VOGM pathophysiology. These advances will improve disease management and genetic counseling, and will stimulate development of targeted therapeutics for VOGMs that may be broadly relevant for other vascular lesions, including AVMs and intracranial aneurysms.

项目总结

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Rho family GTPase signaling through type II p21-activated kinases.

DOI：
10.1007/s00018-022-04618-2
发表时间：
2022-11-19
期刊：
CELLULAR AND MOLECULAR LIFE SCIENCES
影响因子：
8
作者：
Chetty, Ashwin K.;Ha, Byung Hak;Boggon, Titus J.
通讯作者：
Boggon, Titus J.

Structure Determination of SH2-Phosphopeptide Complexes by X-Ray Crystallography: The Example of p120RasGAP.

通过 X 射线晶体学测定 SH2-磷酸肽复合物的结构：以 p120RasGAP 为例。

DOI：
10.1007/978-1-0716-3393-9_5
发表时间：
2023
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
0
作者：
Stiegler,AmyL;Boggon,TitusJ
通讯作者：
Boggon,TitusJ

Cation flux through SUR1-TRPM4 and NCX1 in astrocyte endfeet induces water influx through AQP4 and brain swelling after ischemic stroke.

DOI：
10.1126/scisignal.add6364
发表时间：
2023-06-06
期刊：
Science signaling
影响因子：
7.3
作者：
通讯作者：

Mutation of key signaling regulators of cerebrovascular development in vein of Galen malformations.

DOI：
10.1038/s41467-023-43062-z
发表时间：
2023-11-17
期刊：
NATURE COMMUNICATIONS
影响因子：
16.6
作者：
Zhao, Shujuan;Mekbib, Kedous Y.;van der Ent, Martijn A.;Allington, Garrett;Prendergast, Andrew;Chau, Jocelyn E.;Smith, Hannah;Shohfi, John;Ocken, Jack;Duran, Daniel;Furey, Charuta G.;Hao, Le Thi;Duy, Phan Q.;Reeves, Benjamin C.;Zhang, Junhui;Nelson-Williams, Carol;Chen, Di;Li, Boyang;Nottoli, Timothy;Bai, Suxia;Rolle, Myron;Zeng, Xue;Dong, Weilai;Fu, Po-Ying;Wang, Yung-Chun;Mane, Shrikant;Piwowarczyk, Paulina;Fehnel, Katie Pricola;See, Alfred Pokmeng;Iskandar, Bermans J.;Aagaard-Kienitz, Beverly;Moyer, Quentin J.;Dennis, Evan;Kiziltug, Emre;Kundishora, Adam J.;DeSpenza Jr, Tyrone;Greenberg, Ana B. W.;Kidanemariam, Seblewengel M.;Hale, Andrew T.;Johnston, James M.;Jackson, Eric M.;Storm, Phillip B.;Lang, Shih-Shan;Butler, William E.;Carter, Bob S.;Chapman, Paul;Stapleton, Christopher J.;Patel, Aman B.;Rodesch, Georges;Smajda, Stanislas;Berenstein, Alejandro;Barak, Tanyeri;Erson-Omay, E. Zeynep;Zhao, Hongyu;Moreno-De-Luca, Andres;Proctor, Mark R.;Smith, Edward R.;Orbach, Darren B.;Alper, Seth L.;Nicoli, Stefania;Boggon, Titus J.;Lifton, Richard P.;Gunel, Murat;King, Philip D.;Jin, Sheng Chih;Kahle, Kristopher T.
通讯作者：
Kahle, Kristopher T.

The pseudoGTPase group of pseudoenzymes.