Mutations in MORC2 lead to an axonal form of Charcot-Marie-Tooth (CMT) neuropathy type 2Z. To date, 31 families have been described with mutations in MORC2, indicating that this gene is frequently involved in axonal CMT cases. While the genetic data clearly establish the causative role of MORC2 in CMT2Z, the impact of its mutations on neuronal biology and their phenotypic consequences in patients remains to be clarified. We show that the full-length form of MORC2 is highly expressed in both embryonic and adult human neural tissues and that Morc2 expression is dynamically regulated in both the developing and the maturing murine nervous system. To determine the effect of the most common MORC2 mutations, p.S87L and p.R252W, we used several in vitro cell culture paradigms. Both mutations induced transcriptional changes in patient-derived fibroblasts and when expressed in rodent sensory neurons. These changes were more pronounced and accompanied by abnormal axonal morphology, in neurons expressing the MORC2 p.S87L mutation, which is associated with a more severe clinical phenotype. These data provide insight into the neuronal specificity of the mutated MORC2-mediated phenotype and highlight the importance of neuronal cell models to study the pathophysiology of CMT2Z.

Department of Genomics and Translational Genetics Centro de Investigación Príncipe Felipe Valencia Spain

Department of Neurology Hospital Universitari i Politècnic La Fe and CIBER of Rare Diseases Valencia Spain Department of Medicine University of Valencia Valencia Spain

Department of Neuroscience Karolinska Institutet Stockholm Sweden

Department of Neuroscience Karolinska Institutet Stockholm Sweden Department of Clinical Neuroscience Karolinska Institutet 17165 Stockholm Sweden

Department of Pediatric Neurology DNA Laboratory 2nd Faculty of Medicine Charles University Prague and University Hospital Motol Prague Czech Republic

Department of Pediatric Neurology Hospital Universitario La Paz Madrid Spain

Division of Neurodegeneration Department of Neurobiology Care Sciences and Society Karolinska Institutet Stockholm Sweden The R and D Unit Stiftelsen Stockholms Sjukhemm 14152 Sweden

Northcott Neuroscience Laboratory ANZAC Research Institute Concord NSW Australia Sydney Medical School University of Sydney Sydney NSW Australia

Northcott Neuroscience Laboratory ANZAC Research Institute Concord NSW Australia Sydney Medical School University of Sydney Sydney NSW Australia Molecular Medicine Laboratory Concord Hospital Concord NSW Australia

Unit of Bioinformatics and Biostatistics Centro de Investigación Príncipe Felipe Valencia Spain

Unit of Genetics and Genomics of Neuromuscular and Neurodegenerative Disorders Centro de Investigación Príncipe Felipe Valencia Spain

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