Identification and role of MCM3AP disease gene in neurological disease spectrum and its neuronal modelling

Rare diseases are a heterogenous group of disorders, which together affect a large number of people. These diseases typically have a genetic cause, which affects various cellular processes and pathways. One of the key processes in the cell is RNA metabolism, which is crucial for gene expression. Defects in RNA processing steps contribute to a variety of human diseases ranging from motor neuron diseases to cancer. Most rare diseases currently have no cure. In this dissertation, biallelic variants in Minichromosome maintenance complex 3 associated protein (MCM3AP) gene were found to underlie a neurological syndrome: early-onset peripheral neuropathy with/without intellectual disability. Through international collaboration, patients from multiple families and the disease variants in MCM3AP were identified. Germinal center associated nuclear protein (GANP), encoded by MCM3AP, is a large scaffold protein in the Transcription and Export 2 (TREX-2) complex, which is responsible for the transport of mRNAs from nucleus to the cytoplasm. The effects of different disease-causing variants on GANP abundance on the nuclear envelope were determined, which led to establishment of a genotype/phenotype correlation regarding the severity of the motor phenotype. This research showed that GANP regulates gene expression in a cell type specific manner. In patient fibroblasts, GANP was found to dysregulate genes depending on intron content. In addition, stem cell-based technology and genome editing was utilized to allow modeling of GANP defects in human cultured motor neurons. We found that GANP is a major regulator of gene expression in developing motor neurons, with GANP defects altering the expression of genes related to synaptic functions and resulting in compensatory induction of protein synthesis and mitochondrial pathways. Understanding of the causes and mechanisms of rare diseases is needed for improving diagnostics, therapeutic development and personalized treatments. In this dissertation, the foundation for understanding the mechanisms of MCM3AP-linked neurological syndrome has been established through identification of the causative gene and description of the disease phenotype. The different cellular models including patient-specific motor neurons used in this study have revealed molecular pathways that may be targets for treatment in preclinical trials.