Journal
HUMAN MOLECULAR GENETICS
Volume 28, Issue 10, Pages 1629-1644Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddz006
Keywords
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Funding
- Instituto de Salud Carlos III (ISCIII) - Subdireccion General de Evaluacion y Fomento de la Investigacion [PI15/00187, PI16/00403]
- FEDER funds
- Ramon Areces Foundation [CIVP17A2810]
- Generalitat Valenciana [PROMETEO/2018/135]
- AFM-Telethon [21500]
- National Health and Medical Research Council of Australia [APP1046680]
- Czech Health Research Council [AZV16-30206A]
- Swedish StratNeuro program grant
- Swedish Research Council [2015-02394]
- ISCIII
- Centro de Investigacion Principe Felipe [CPII14/00002]
- FPU-PhD fellowship - Spanish Ministry of Education, Culture and Sport [FPU15/00964]
- Swedish Research Council [2015-02394] Funding Source: Swedish Research Council
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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.
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