Investigation of pathomechanisms of Borjeson-Forssman-Lehmann syndrome

最近，我们在几个智力残疾的女性患者中发现了PHF6的新生突变，这些患者的临床表现非常明显。此前，PHF6突变与x连锁隐性Borjeson-Forssman-Lehmann综合征（BFLS）有关。除了在PHF6新发突变的女性患者中非常独特的表型外，与男性BLFS的临床重叠，有趣的是，也与由SWI/ snf复合物亚基突变引起的Coffin-Siris综合征（CSS）的临床重叠是可以识别的。PHF6包含两个植物同源域样结构域（PHD）结构域，这些结构域来自染色质相互作用蛋白，定位于细胞核，并与PAF1转录起始复合物和NuRD复合物相互作用，NuRD复合物是一种多功能表观遗传调节剂。在这项研究中，我们将研究PHF6的作用和功能以及新生突变的功能后果。我们将：1；通过进一步识别患者，进一步描绘BFLS的基因型和表型谱。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的病理机制有了新的认识。2. 利用转录组分析和ChIP-Seq建立PHF6靶基因和通路的全面图谱，并确定其在调节染色质和转录相关过程中的作用。3. 通过使用直接转分化或诱导多能干细胞从患者成纤维细胞中生成神经元祖细胞或神经元，以评估其形态、增殖和迁移，获得对PHF6神经元作用的具体见解。我们期望对PHF6在染色质和转录调控的基本过程中的作用以及导致BFLS各种表型的病理机制有新的见解。

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.