Deciphering molecular mechanisms of CHAMP1 deficiency-associated developmental delay

• Applicant: Professor Dr. Davor Lessel
• Subject Area: Human Genetics
• Term: from 2018 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 409793010

The rapid advances of new technologies including massively parallel sequencing have allowed the elucidation of a large number of previously undiagnosed rare inherited disorders during the last years. This holds especially true for children with seemingly sporadic, non-syndromic or mild dysmorphic forms of neurodevelopmental disorders, including intellectual disability, developmental delay and autism spectrum disorder. However, the molecular and cellular consequences of the identified mutations and associated protein disturbances remain mostly unknown.Applying a trio whole-exome sequencing approach we have recently established deleterious mutations in CHAMP1 as a novel monogenic cause of a developmental disorder (DD). This syndrome is characterized by intellectual disability, delayed motor development with particularly severe abnormalities in speech development. CHAMP1 is a zinc-finger protein involved in the maintenance of kinetochore-microtubule attachment during mitosis and the regulation of accurate chromosome segregation, both of which are crucial for proper cortical and mental development. Our initial functional characterization of patient-derived primary fibroblasts suggests an additional, and previously unknown, role of CHAMP1 in the maintenance of genomic stability and CHK1-CDK1 signaling pathway. Notably, abnormal chromosome segregation during mitosis can result in chromosomal instability which is considered as the driving force of tumorigenesis. Indeed, somatic focal deletions involving CHAMP1 are found in around 12% of highly aggressive prostate adenocarcinomas.Here we aim to further decipher CHAMP1-mediated biological processes by performing in-depth functional characterization of patient-derived primary cell lines, followed by complementary in-vitro analyses including analyses in genome-edited cells. Specifically we want to further delineate the role of CHAMP1 in the CHK1-CDK1 signaling pathway, investigate its putative role in DNA damage response pathways and DNA replication. In addition, we plan to elucidate whether inhibition of CHAMP1 can be exploited in cancer treatment following a synthetic lethality approach. Taken together, these studies aim to unravel molecular mechanisms involved in CHAMP1-associated disorder and may have direct implications in clinical management of affected individuals. Moreover, this knowledge may additionally lead to the identification of targets for developing novel drugs for treating various forms of cancer.

• DFG Programme: Research Grants