Investigation of pathomechanisms of Borjeson-Forssman-Lehmann syndrome

• Applicant: Professorin Dr. Christiane Zweier
• Subject Area: Human Genetics
• Term: from 2016 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 318839285

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.

• DFG Programme: Research Grants