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Investigation of pathomechanisms of Borjeson-Forssman-Lehmann syndrome

Borjeson-Forssman-Lehmann 综合征发病机制的研究

基本信息

批准号：
318839285
负责人：
Professorin Dr. Christiane Zweier
金额：
--
依托单位：
Abteilung für Humangenetik
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2016
资助国家：
德国
起止时间：
2015-12-31 至 2019-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/318839285?language=en
关键词：
Investigation pathomechanisms Borjeson Forssman Lehmann

项目摘要

Recently, we identified de novo mutations in PHF6 in several female patients with intellectual disability and a very distinct, recognizable clinical appearance. Previously, mutations in PHF6 were implicated in the X-linked recessive Borjeson-Forssman-Lehmann syndrome (BFLS). Apart from the very distinct phenotype in the female patients with de novo mutations in PHF6, clinical overlap with BLFS in males and, interestingly, also with Coffin-Siris syndrome (CSS), caused by mutations in subunits of the SWI/SNF-complex, was recognizable. PHF6 contains two plant-homeodomain-like (PHD) domains, known from chromatin-interacting proteins, localizes to the nucleus, and interacts with the PAF1 transcription initiation complex and with the NuRD complex, a multifunctional epigenetic regulator. In this study we will investigate both the role and function of PHF6 and the functional consequences of the de novo mutations. We will: 1. further delineate the genotypic and phenotypic spectrum of BFLS by identifying further patients. 2. gain new insights into the pathomechanisms of BFLS by investigating individual consequences of mutations and by characterizing the role of PHF6 in neuronal migration disorders. 2. use transcriptome analyses and ChIP-Seq to establish a comprehensive picture of target genes and pathways of PHF6 and to define its role in regulating chromatin and transcription related processes. 3. gain specific insights into the neuronal role of PHF6 by using either direct transdifferentiation or induced pluripotent stem cells to generate neuronal progenitor cells or neurons from patient fibroblasts to evaluate their morphology, proliferation and migration. We expect new insights both into the role of PHF6 in essential processes of chromatin- and transcription regulation and into the pathomechanisms that lead to the various phenotypes of BFLS.

最近，我们在几名智力残疾的女性患者中发现了PHF6的从头突变，这些患者具有非常独特的、可识别的临床表现。此前，PHF6的突变与X连锁隐性Borjeson-Forssman-Lehmann综合征(BFLS)有关。除了PHF6基因从头突变的女性患者具有非常独特的表型外，男性患者的临床表现与BLFS重叠，有趣的是，还与由SWI/SNF-复合体亚单位突变引起的Coffin-Siris综合征(CSS)重叠。PHF6含有两个植物同源结构域(PHD)结构域，从染色质相互作用蛋白中已知，定位于细胞核，并与PAF1转录起始复合体和多功能表观遗传调节因子NuRD复合体相互作用。在这项研究中，我们将研究PHF6的作用和功能以及从头突变的功能后果。我们将：1.通过鉴定更多的患者，进一步描述BFLS的基因型谱和表型谱。2.通过研究突变的个体后果和表征PHF6在神经元迁移障碍中的作用，对BFLS的发病机制有了新的见解。2.利用转录组分析和芯片序列分析，建立PHF6靶基因和通路的全面图谱，并确定其在染色质和转录相关过程中的调控作用。3.通过直接转分化或诱导多能干细胞从患者成纤维细胞中产生神经前体细胞或神经元，以评估其形态、增殖和迁移，从而获得对PHF6的神经元作用的具体见解。我们期待着对PHF6在染色质和转录调节的基本过程中的作用以及导致BFLS各种表型的病理机制的新见解。