Identification and molecular characterization of somatic mutations in MCD

MCD 体细胞突变的鉴定和分子特征

基本信息

  • 批准号:
    10666977
  • 负责人:
  • 金额:
    $ 72.1万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2016
  • 资助国家:
    美国
  • 起止时间:
    2016-09-30 至 2028-05-31
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY Genetic mutations causing disease may be inherited, newly acquired in parental gametes and present in the zygote, or acquired at some point in development after fertilization. The burden and localization of a post- zygotically acquired mutation depends on when the mutation arises. Malformations of cortical development (MCD) are a group of disorders characterized by a range of morphological and structural abnormalities of the cerebral cortex reflecting errors in embryonic cortical development. MCD are associated with refractory epilepsy as well as intellectual disability and may require the surgical removal of the affected tissue for seizure control. There is increasing recognition that post-zygotically acquired somatic mutations occurring in neuroglial progenitor cells can result in a cortical brain malformation. In the previous funding period of this grant, we made significant progress identifying and molecularly characterizing a series of pathogenic post-zygotically acquired somatic variants in the resected brain tissue of individuals with an epilepsy-associated cortical brain malformation. Most notably we identified and functionally characterized the first gene associated with focal cortical dysplasia type I, SLC35A2, and made significant advancements in the understanding of the somatic genetic landscape across MCD. The overarching objective for the next funding cycle is to continue to identify somatic variants across MCD and to functionally characterize the effects of novel variants associated with different types of MCD on cortical development. In Aim 1, we will continue to collect resected brain tissue specimens from individuals with MCD for high-depth exome or targeted gene sequencing. The goal of Aim 1 is to identify novel genes involved in MCD and to ascertain the subset of exome-negative cases for use in Aim 2. In Aim 2, we will use highly sensitive duplex sequencing to detect very low-level somatic variants and PCR-free whole-genome sequencing to detect somatic short tandem repeat variants and intermediately sized somatic copy number variants in exome-negative MCD cases. The goal of Aim 2 is to determine the contribution of these classes of somatic variants that are routinely missed due to the limitations of standard short-read exome sequencing in the overall somatic genetic risk of MCD. Finally, Aim 3 will evaluate the functional consequences of knocking out newly identified MCD genes harboring somatic loss-of-function variants on neuronal morphology, neuronal migration, and ultimately cerebral cortical development in the developing mouse brain. These studies will: (i) continue our in-depth assessment of the role of somatic mutations across MCD subtypes, (ii) identify novel genes/pathways involved in cortical development, (iii) use complementary in vitro, ex vivo, and in vivo models to understand the role of novel genes implicated cortical development, and (iv) establish biomarkers and platforms that can be used in the future for screening of compounds to possibly prevent or improve the prognosis of MCD.
项目摘要 引起疾病的基因突变可能是遗传的,在父母配子中新获得的,并存在于 受精卵,或在受精后发育的某个阶段获得。一个岗位的负担和定位-- 合子获得性突变取决于突变发生的时间。皮质发育畸形 (MCD)是一组以一系列的形态和结构异常为特征的疾病, 反映胚胎皮层发育错误的大脑皮层。MCD与难治性 癫痫以及智力残疾,可能需要手术切除受影响的组织进行癫痫发作 控制越来越多的人认识到,发生在神经胶质细胞中的合子后获得性体细胞突变, 祖细胞会导致大脑皮层畸形在上一个资助期内,我们 取得了重大进展,确定和分子特征的一系列致病后合子 癫痫相关皮质脑患者切除的脑组织中获得性体细胞变异 畸形最值得注意的是,我们确定了第一个与局灶性脑梗死相关的基因,并对其进行了功能表征。 皮质发育不良I型,SLC35A2,并取得了显着的进展,在理解体细胞 遗传景观。下一个供资周期的首要目标是继续查明 MCD的体细胞变异,并在功能上表征与 不同类型MCD对皮质发育的影响。在目标1中,我们将继续收集切除的脑组织, 来自MCD患者的样本进行高深度外显子组或靶向基因测序。目标1的目标是 以鉴定涉及MCD的新基因,并确定用于Aim 2的外显子组阴性病例的子集。 在目标2中,我们将使用高灵敏度的双链测序来检测非常低水平的体细胞变异, 全基因组测序,以检测体细胞短串联重复序列变异和中等大小的体细胞 外显子组阴性MCD病例中的拷贝数变异。目标2的目标是确定 由于标准短读外显子组的限制,这些类型的体细胞变体通常被遗漏, 测序在MCD的整体体细胞遗传风险中的作用。最后,目标3将评估功能后果 敲除新发现的MCD基因,这些基因在神经元上携带体细胞功能丧失变体, 形态学、神经元迁移和最终发育中的小鼠大脑中的大脑皮质发育。 这些研究将:(i)继续深入评估体细胞突变在MCD中的作用, 亚型,(ii)鉴定参与皮质发育的新基因/途径,(iii)在体外使用互补的, 离体和体内模型,以了解涉及皮质发育的新基因的作用,以及(iv) 建立生物标志物和平台,可用于在未来筛选化合物, 预防或改善MCD的预后。

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
LUSTR: a new customizable tool for calling genome-wide germline and somatic short tandem repeat variants.
  • DOI:
    10.1186/s12864-023-09935-9
  • 发表时间:
    2024-01-26
  • 期刊:
  • 影响因子:
    4.4
  • 作者:
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Peter B Crino其他文献

Peter B Crino的其他文献

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{{ truncateString('Peter B Crino', 18)}}的其他基金

Somatic Mutation in Intractable Focal Epilepsy
难治性局灶性癫痫的体细胞突变
  • 批准号:
    10788846
  • 财政年份:
    2023
  • 资助金额:
    $ 72.1万
  • 项目类别:
KPTN Loss and Megalencephaly: mTOR Activation as Therapeutic Target
KPTN 丢失和巨脑畸形:mTOR 激活作为治疗靶点
  • 批准号:
    10375917
  • 财政年份:
    2022
  • 资助金额:
    $ 72.1万
  • 项目类别:
KPTN Loss and Megalencephaly: mTOR Activation as Therapeutic Target
KPTN 丢失和巨脑畸形:mTOR 激活作为治疗靶点
  • 批准号:
    10544536
  • 财政年份:
    2022
  • 资助金额:
    $ 72.1万
  • 项目类别:
Somatic Mutation in Intractable Focal Epilepsy
难治性局灶性癫痫的体细胞突变
  • 批准号:
    10662245
  • 财政年份:
    2020
  • 资助金额:
    $ 72.1万
  • 项目类别:
Somatic Mutation in Intractable Focal Epilepsy
难治性局灶性癫痫的体细胞突变
  • 批准号:
    10888458
  • 财政年份:
    2020
  • 资助金额:
    $ 72.1万
  • 项目类别:
Defining disease mechanisms in SLC35A2 epilepsy
定义 SLC35A2 癫痫的疾病机制
  • 批准号:
    10058871
  • 财政年份:
    2020
  • 资助金额:
    $ 72.1万
  • 项目类别:
Defining disease mechanisms in SLC35A2 epilepsy
定义 SLC35A2 癫痫的疾病机制
  • 批准号:
    10609847
  • 财政年份:
    2020
  • 资助金额:
    $ 72.1万
  • 项目类别:
Defining disease mechanisms in SLC35A2 epilepsy
定义 SLC35A2 癫痫的疾病机制
  • 批准号:
    10191063
  • 财政年份:
    2020
  • 资助金额:
    $ 72.1万
  • 项目类别:
Defining disease mechanisms in SLC35A2 epilepsy
定义 SLC35A2 癫痫的疾病机制
  • 批准号:
    10379373
  • 财政年份:
    2020
  • 资助金额:
    $ 72.1万
  • 项目类别:
Somatic Mutation in Intractable Focal Epilepsy
难治性局灶性癫痫的体细胞突变
  • 批准号:
    10453576
  • 财政年份:
    2020
  • 资助金额:
    $ 72.1万
  • 项目类别:

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