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Identification and functional interrogation of neurodevelopmental disease genes at multigene loci

机译：多基因位点神经发育疾病基因的鉴定和功能研究

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摘要

The continual discovery of new disease loci through characterization of copy number variants (CNVs) has demonstrated that structural rearrangements play a large role in neurodevelopmental disorders (NDDs). A clear understanding of underlying mechanisms is crucial for NDD treatments. Furthermore, given the reduced penetrance and variable expressivity of these CNVs, creating ways to model this complexity is likewise important for development of effective therapeutics.;In the first part of my thesis, I identified a rare inherited duplication at 19p13.12 in an individual with autism and intellectual disability and in two unaffected family members who are all macrocephalic. Consideration alongside overlapping CNV events in the literature supports a strong relationship between gene dosage at this locus and head size. Using deletion mapping, we narrowed down the critical region to two genes: AKAP8 and AKAP8L. Both are members of the AKAP family, a group already implicated in autism. These findings support the idea that gene dosage at 19p13.12, and AKAP8 and/or AKAP8L in particular, play an important role in modulation of head size and may contribute to NDD risk. Exome sequencing of the case family identified a likely disruptive mutation in TPTE/ PTEN2, a PTEN homologue, which may likewise contribute to both macrocephaly and NDD risk.;In the second part of my thesis, I model the 15g11.2 (BP1-2) deletion, a CNV known to increase risk for epilepsy and schizophrenia, using two cell types. We first examined lymphoblastoid cells from BP1-2 deletion carriers and controls, but found no in differences in multiple cellular and molecular endpoints. We then knocked down CYFIP1, a gene within the BP1-2 locus, in human neural progenitors derived from healthy BP1-2 copy number neutral donors. Transcriptional profiling revealed alteration of cytoskeleton genes, FMRP targets, and postsynaptic density genes in response to CYFIP1 knockdown. Furthermore, schizophrenia and epilepsy genes were overrepresented among dysregulated genes, and the magnitude of these effects differed between lines. Lastly, we showed that phenytoin, an anti-seizure drug, increased levels of CYFIP1 in control NPCs.;Through the strategies described above, we identified and genetically and functionally characterized likely contributory genes within two separate disease-associated loci.
机译：通过表征拷贝数变异（CNV）不断发现新的疾病位点，已证明结构重排在神经发育障碍（NDD）中发挥重要作用。清楚了解基本机制对于NDD治疗至关重要。此外，考虑到这些CNV的渗透率降低和表达可变性，建立模拟这种复杂性的方法对于开发有效的治疗方法同样重要。；在论文的第一部分，我在个体中发现了罕见的19p13.12遗传重复患有自闭症和智力障碍，并且两个未受影响的家庭成员均为大头畸形。文献中考虑重叠CNV事件，这支持了该基因座处的基因剂量与头部大小之间的密切关系。使用删除映射，我们将关键区域缩小为两个基因：AKAP8和AKAP8L。两者都是AKAP家族的成员，该家族已经牵涉自闭症。这些发现支持了这样的想法，即19p13.12的基因剂量，尤其是AKAP8和/或AKAP8L，在调节头部大小中起重要作用，并且可能导致NDD风险。该病例家族的外显子组测序发现TPTE / PTEN2是PTEN同源物，可能具有破坏性突变，可能同样导致大头畸形和NDD风险。；在论文的第二部分，我对15g11.2（BP1-2）进行了建模。 ），这是一种使用两种细胞类型已知会增加癫痫和精神分裂症风险的CNV。我们首先检查了来自BP1-2缺失携带者和对照的淋巴母细胞，但未发现多个细胞和分子终点存在差异。然后，我们在源自健康BP1-2拷贝数中性供体的人神经祖细胞中敲除CYFIP1，这是BP1-2基因座内的一个基因。转录分析揭示响应CYFIP1敲低的细胞骨架基因，FMRP目标和突触后密度基因的变化。此外，精神分裂症和癫痫基因在失调的基因中被过度表达，并且这些效应的强度在品系之间有所不同。最后，我们表明苯妥英钠是一种抗癫痫药，可提高对照NPC中CYFIP1的水平。通过上述策略，我们在两个独立的疾病相关基因座中鉴定了可能的贡献基因，并对其进行了遗传和功能表征。

著录项

  • 作者

    Nebel, Rebecca A.;

  • 作者单位

    Yeshiva University.;

  • 授予单位 Yeshiva University.;
  • 学科 Genetics.;Neurosciences.;Developmental biology.
  • 学位 Ph.D.
  • 年度 2016
  • 页码 252 p.
  • 总页数 252
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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