Genomic Insights into the Neurobiology of Cerebral Palsy

脑瘫神经生物学的基因组见解

• 批准号: 10614370
• 负责人: Michael C Kruer
• 金额: $ 73.34万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10614370
• 关键词: Adolescent; Advocacy; Affect; Area; Asphyxia Neonatorum; Benign; Biochemical; Biological Assay; Biological Models; Brain; Brain Hypoxia-Ischemia; Candidate Disease Gene; Cell Line; Cellular biology; Cerebral Palsy; Child; Collaborations; Complement; Copy Number Polymorphism; DNA; Data; Development; Diagnosis; Diagnostic; Disease; Drosophila genus; Environmental Risk Factor; Epilepsy; Fibroblasts; Gene set enrichment analysis; Genes; Genetic; Genetic Predisposition to Disease; Genome; Genomics; Goals; Human; Impairment; Individual; Infection; Inheritance Patterns; Intellectual functioning disability; International; Lead; Life; Mammalian Cell; Maps; Modeling; Molecular; Molecular Target; Motor; Mutation; Nervous System; Neurobiology; Neurodevelopmental Disorder; Neuroglia; Neurons; Open Reading Frames; Oxygen; Parents; Participant; Pathway Analysis; Pathway interactions; Patients; Phenotype; Polynomial Models; Prevalence; Process; Publishing; Recurrence; Research; Research Personnel; Risk; Series; Single Nucleotide Polymorphism; Surface; System; Systems Biology; Validation; Variant; Work; Yeasts; autism spectrum disorder; causal variant; cohort; de novo mutation; deprivation; developmental neurobiology; exome; exome sequencing; experimental study; falls; fly; genome editing; genome-wide; hypoxic ischemic injury; improved; insertion/deletion mutation; insight; knock-down; loss of function; lymphoblast; motor impairment; mutant; neurodevelopment; novel; overexpression; premature; prenatal; public health relevance; risk variant; therapeutic development; validation studies

PROJECT SUMMARY/ABSTRACT Cerebral palsy (CP) is a major neurodevelopmental disorder (prevalence 3:1000) that alters the course of normal brain development and impairs motor function. Although both prematurity and lack of oxygen to the developing brain are well-known causes of CP, current estimates suggest that up to one third of cases of CP may be genetic in origin. This represents a major shift for the field, which has almost exclusively focused on environmental contributions to date. Only a handful of genetic causes of CP are known, suggesting research in this area may be ‘scratching the surface’ of a vast genomic landscape, comparable to that seen in other neurodevelopmental disorders such as autism, intellectual disability and epilepsy. Although other inheritance patterns likely lead to CP in some patients, the central hypothesis of this proposal is that for many individuals with CP, mutations in a single gene may account for their condition. This project unites clinicians, researchers and advocacy stakeholders in order to discover and validate novel genetic causes of CP. The research team will employ whole exome sequencing to comb through the protein- coding regions of the genome to find causative mutations in previously unrecognized genes relevant to CP. We focus on individuals with cryptogenic CP (i.e. CP of unknown cause) and thus our cohort is highly enriched for strong genetic effect sizes. Our preliminary data indicate that deleterious mutations substantially contribute to cerebral palsy, and identify multiple high-confidence “cerebral palsy genes.” These results suggest that although genes implicated in cases of cryptogenic CP are diverse, many map to common pathways. The goal of this application is to extend our preliminary findings to encompass a much larger cohort, providing the power required to define fundamental aspects of the genetic basis of CP. Whole exome sequencing of 500 parent-child trios is proposed to accomplish the following aims: 1) discover new genes and pathways that lead to CP when mutations occur; 2) pinpoint genes crucial for normal motor neurodevelopment; 3) distinguish bona fide mutations from benign DNA variants through a series of validation experiments in multiple model systems. Impact: Successful completion of the proposed aims will allow identification of new ‘CP genes’ with immediate diagnostic implications. These findings will also allow the construction of a genomic “roadmap” of shared pathways connecting genetic forms of CP. In so doing, these studies will provide a window into CP neurobiology that will compare and contrast pathways between genetic and environmental forms of CP. Finally, this work will generate important primary data that will be shared within the recently established International Cerebral Palsy Genomics Consortium, spearheading international collaboration in CP genomics.

项目总结/摘要 脑性瘫痪（CP）是一种主要的神经发育障碍（患病率3：1000），它改变了大脑的发育过程。 正常的大脑发育和损害运动功能。虽然早产和缺氧都是 发育中的大脑是CP的众所周知的原因，目前的估计表明，多达三分之一的CP病例 可能是遗传的。这代表了该领域的一个重大转变，该领域几乎完全专注于 环境贡献至今。只有少数遗传原因的CP是已知的，这表明研究， 这一区域可能是一个巨大的基因组景观的“表面”，与其他基因组景观中看到的可比较。 神经发育障碍，如自闭症、智力残疾和癫痫。虽然其他遗产 模式可能导致CP在某些患者中，该建议的中心假设是，对于许多个体， 对于CP，单个基因的突变可能是导致其病情的原因。 该项目联合临床医生，研究人员和倡导利益相关者，以发现和验证新的 CP的遗传原因研究小组将使用整个外显子组测序来梳理蛋白质- 基因组的编码区，以发现以前未识别的与CP相关的基因中的致病突变。我们 重点关注患有隐源性CP（即原因不明的CP）的个体，因此我们的队列高度富集了 强大的遗传效应。 我们的初步数据表明，有害突变在很大程度上导致脑瘫，并确定 多个高置信度的“脑瘫基因”这些结果表明，虽然基因牵连的情况下， 隐源性CP具有多样性，许多映射到共同的途径。此应用程序的目标是扩展我们的 初步调查结果，以涵盖更大的队列，提供所需的权力，以确定基本 CP的遗传基础。建议对500个亲子三人组进行全外显子组测序， 完成以下目标：1）发现新的基因和途径，导致CP突变发生时; 2） 精确定位对正常运动神经发育至关重要的基因; 3）区分真正的突变和良性突变 通过在多个模型系统中进行的一系列验证实验来确定DNA变体。 影响：成功完成拟议的目标将允许识别新的“CP基因”， 诊断意义这些发现还将允许构建一个共享的基因组“路线图”。 连接CP遗传形式的途径。这样做，这些研究将提供一个窗口， 神经生物学将比较和对比遗传和环境形式的CP之间的途径。 最后，这项工作将产生重要的原始数据，这些数据将在最近建立的 国际脑瘫基因组学联盟，引领脑瘫基因组学的国际合作。

项目成果

Intrathecal magnesium delivery for Mg++-insensitive NMDA receptor activity due to GRIN1 mutation.

• DOI: 10.1186/s13023-023-02756-9
• 发表时间: 2023-08-03
• 期刊: ORPHANET JOURNAL OF RARE DISEASES
• 影响因子: 3.7
• 作者: Lewis, Sara A.;Shetty, Sheetal;Gamble, Sean;Heim, Jennifer;Zhao, Ningning;Stitt, Gideon;Pankratz, Matthew;Mangum, Tara;Marku, Iris;Rosenberg, Robert B.;Wilfong, Angus A.;Fahey, Michael C.;Kim, Sukhan;Myers, Scott J.;Appavu, Brian;Kruer, Michael C.
• 通讯作者: Kruer, Michael C.

The phenotypic spectrum of PCDH12 associated disorders - Five new cases and review of the literature.

• DOI: 10.1016/j.ejpn.2021.10.011
• 发表时间: 2022-01
• 期刊: EUROPEAN JOURNAL OF PAEDIATRIC NEUROLOGY
• 影响因子: 3.1
• 作者: Fazeli, Walid;Bamborschke, Daniel;Moawia, Abubakar;Bakhtiari, Somayeh;Tafakhori, Abbas;Giersdorf, Matthias;Hahn, Andreas;Weik, Anja;Kolzter, Kirsten;Shafiee, Sajad;Jin, Sheng Chih;Koerber, Friederike;Lee-Kirsch, Min Ae;Darvish, Hossein;Cirak, Sebahattin;Kruer, Michael C.;Koy, Anne
• 通讯作者: Koy, Anne

Insights From Genetic Studies of Cerebral Palsy.

脑瘫遗传研究的见解。

• DOI: 10.3389/fneur.2020.625428
• 发表时间: 2020
• 期刊: Frontiers in neurology
• 影响因子: 3.4
• 作者: Lewis SA;Shetty S;Wilson BA;Huang AJ;Jin SC;Smithers-Sheedy H;Fahey MC;Kruer MC
• 通讯作者: Kruer MC

SLITRK2 variants associated with neurodevelopmental disorders impair excitatory synaptic function and cognition in mice.

• DOI: 10.1038/s41467-022-31566-z
• 发表时间: 2022-07-15
• 期刊: Nature communications
• 影响因子: 16.6

A biallelic loss-of-function variant in TMEM147 causes profound intellectual disability and spasticity.

TMEM147 中的双等位基因功能丧失变异会导致严重的智力障碍和痉挛。

• DOI: 10.1007/s10048-023-00734-8
• 发表时间: 2023
• 期刊: Neurogenetics
• 影响因子: 2.2
• 作者: Ghorashi,Tahereh;Darvish,Hossein;Bakhtiari,Somayeh;Tafakhori,Abbas;Kruer,MichaelC;Mozdarani,Hossein
• 通讯作者: Mozdarani,Hossein