Related Experiment Video
Updated: Oct 15, 2025
Modeling Age-Associated Neurodegenerative Diseases in Caenorhabditis elegans
Published on: August 15, 2020
Morc2a p.S87L mutant mice develop peripheral and central neuropathies associated with neuronal DNA damage and
Geon Seong Lee1, Geon Kwak2,3, Ji Hyun Bae1
1Graduate School of International Agricultural Technology and Institute of Green Bio Science and Technology, Seoul National University, 1447 Pyeongchang-Ro, Daewha, Pyeongchang, Kangwon 25354, South Korea.
Abstract:
The microrchidia (MORC)-family CW-type zinc finger 2 (MORC2) gene is related to DNA repair, adipogenesis and epigenetic silencing via the human silencing hub (HUSH) complex. MORC2 missense mutation is known to cause peripheral neuropathy of Charcot-Marie-Tooth disease type 2 Z (CMT2Z). However, there have been reports of peripheral and central neuropathy in patients, and the disease has been co-categorized with developmental delay, impaired growth, dysmorphic facies and axonal neuropathy (DIGFAN). The etiology of MORC2 mutation-mediated neuropathy remains uncertain. Here, we established and analyzed Morc2a p.S87L mutant mice. Morc2a p.S87L mice displayed the clinical symptoms expected in human CMT2Z patients, such as axonal neuropathy and skeletal muscle weakness. Notably, we observed severe central neuropathy with cerebella ataxia, cognition disorder and motor neuron degeneration in the spinal cord, and this seemed to be evidence of DIGFAN. Morc2a p.S87L mice exhibited an accumulation of DNA damage in neuronal cells, followed by p53/cytochrome c/caspase 9/caspase 3-mediated apoptosis. This study presents a new mouse model of CMT2Z and DIGFAN with a Morc2a p.S87L mutation. We suggest that neuronal apoptosis is a possible target for therapeutic approach in MORC2 missense mutation. This article has an associated First Person interview with the first author of the paper.
Insights
A new mouse model reveals that mutations in the microrchidia (MORC2) gene cause both peripheral and central nervous system damage, leading to Charcot-Marie-Tooth disease type 2 Z (CMT2Z) and DIGFAN. This suggests targeting neuronal apoptosis may treat these conditions.
Area of Science:
- Genetics
- Neuroscience
- Molecular Biology
Background:
- The microrchidia (MORC)-family CW-type zinc finger 2 (MORC2) gene plays roles in DNA repair and epigenetic regulation via the HUSH complex.
- MORC2 missense mutations are linked to Charcot-Marie-Tooth disease type 2 Z (CMT2Z), a peripheral neuropathy, and sometimes co-occur with developmental disorders (DIGFAN).
- The precise mechanisms underlying MORC2 mutation-induced neuropathy are not fully understood.
Purpose of the Study:
- To establish and analyze a mouse model with a Morc2a p.S87L mutation to investigate MORC2-related neuropathies.
- To elucidate the pathological mechanisms of MORC2 mutations in the nervous system.
- To explore potential therapeutic targets for MORC2-mediated neurological disorders.
Main Methods:
- Generation and characterization of Morc2a p.S87L mutant mice.
- Assessment of clinical symptoms, including neurological function and skeletal muscle strength.
- Histopathological analysis of the central and peripheral nervous systems, focusing on DNA damage and apoptosis pathways in neuronal cells.
Main Results:
- Morc2a p.S87L mice exhibited peripheral neuropathy, skeletal muscle weakness, and central nervous system deficits, including cerebellar ataxia, cognitive impairment, and spinal motor neuron degeneration.
- These findings in the mouse model mirror symptoms observed in human CMT2Z and DIGFAN patients.
- Accumulation of DNA damage and activation of the p53-mediated apoptotic pathway (cytochrome c, caspase 9, caspase 3) were observed in neuronal cells of the mutant mice.
Conclusions:
- The Morc2a p.S87L mutant mouse serves as a valuable model for studying CMT2Z and DIGFAN.
- MORC2 mutations induce neuronal apoptosis, suggesting this pathway as a potential therapeutic target for related neuropathies.
- Further research into MORC2 function and mutation effects is warranted for developing effective treatments.
More Related Videos
06:35In Vivo Electrophysiological Measurement of Compound Muscle Action Potential from the Forelimbs in Mouse Models of Motor Neuron Degeneration
Published on: June 15, 2018
06:49A Quick Phenotypic Neurological Scoring System for Evaluating Disease Progression in the SOD1-G93A Mouse Model of ALS
Published on: October 6, 2015