Abstract
ABSTRACTThe 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.
Highlights
Neuropathy is caused by nerve damage and leads to symptoms such as weakness, numbness or pain
Because MORC2 is related to DNA repair, we evaluated earlystage DNA damage by analyzing γH2AX and p53 expression in mice. γH2AX seemed to be highly expressed in the spinal cord, heart and quadriceps femoris (Quad) muscle of B6.microrchidia 2A (Morc2a) S87L/+ mice
We developed B6.Morc2a S87L/+ mice, which represent a good Charcot-Marie-Tooth disease (CMT) type 2 Z (CMT2Z) and DIGFAN model
Summary
Neuropathy is caused by nerve damage and leads to symptoms such as weakness, numbness or pain. Charcot-Marie-Tooth disease (CMT) is a hereditary motor and sensory neuropathy commonly inherited as peripheral neuropathy (Tazir et al, 2014). Patients with CMT generally develop distal muscle weakness and atrophy, distal sensory loss, weak ankle dorsiflexion, depressed tendon reflexes and high-arched feet (McDonald, 2012). The recently reported CMT type 2 Z (CMT2Z) is an autosomal-dominant peripheral neuropathy that is caused by a mutation in the microrchidia (MORC)-family CW-type zinc finger 2 (MORC2) gene (Sevilla et al, 2016). MORC2 functions as a transcriptional repressor when overexpressed and leads to the development of several phenotypes through interaction with other genes (Wang et al, 2010). MORC2 has several functions, such as DNA repair by interaction with p21-activated kinase 1 (Li et al, 2012), adipogenesis and lipid homeostasis via ATP citrate lyase phosphorylation and activation (Sanchez-Solana et al, 2014), and epigenetic silencing via interaction with the HUSH complex (Tchasovnikarova et al, 2017)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
