Morc2a p.S87L mutant mice develop peripheral and central neuropathies associated with neuronal DNA damage and apoptosis

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.

The HUSH complex controls brain architecture and protocadherin fidelity

“…Some of the observed mouse phenotypes including growth retardation, craniofacial dysmorphisms, and weakness are similar to human patients with MORC2 mutations ( 18 ), while others are opposite (microcephaly versus macrocephaly), which might stem from the fact that patients carry heterozygous MORC2 mutations in the adenosine triphosphatase (ATPase) module resulting in apparent hyperactivation of HUSH silencing. A heterozygous full-body p.S87L Morc2a mouse mutant (mimicking one of the various hyperactivating patient mutations) showed phenotypes similar to our Morc2a -deficient mice concerning locomotive dysfunction and activity, but featured neuronal apoptosis, smaller cerebella, cerebellar ataxia, and spinal cord motor neuron degeneration ( 39 ). It remains to be investigated whether the p.S87L Morc2a mice also exhibit deregulation of clustered protocadherins.…”

Microrchidia CW-Type Zinc Finger 2, a Chromatin Modifier in a Spectrum of Peripheral Neuropathies

“…It seems imperative to test each known mutation for its impact on MORC2 ATPase activity while taking into account the autosomal dominant character of the disease. Although the mouse model of Lee et al (2021) is an initial and important step, new animal models are required to cover the variability of MORC2-related neuropathic mutations. On the other hand, the variability of genomic insertion of transposable elements among individuals, the combination of multiple genomic mutations and the gender could also influence the severity and the onset of the disease.…”

“…This mouse model develops axonal neuropathy, locomotor dysfunction, skeletal muscle weakness but also cerebellar ataxia and motor neuron degeneration, thus recapitulating the features of central and peripheral neuropathies associated with MORC2 mutations in humans. At the molecular level, both peripheral and central nervous system neurons display an accumulation of DNA damage coupled with neuronal apoptosis (Lee et al, 2021). This could partially explain the peripheral neuropathy while highlighting the possible impact on the CNS leading to DIGFAN syndrome.…”

“…Mouse Morc2 and human MORC2 genes exhibit ∼97% amino acid similarity in the ATPase domain. Using CRISPR/Cas9-mediated genome editing, a recent study has developed a Morc2a c.C260T knock-in mouse model which leads to the generation of heterozygous Morc2 p.S87L mice (Lee et al, 2021). This mouse model develops axonal neuropathy, locomotor dysfunction, skeletal muscle weakness but also cerebellar ataxia and motor neuron degeneration, thus recapitulating the features of central and peripheral neuropathies associated with MORC2 mutations in humans.…”

First person – Geon Seong Lee

“… ABSTRACT First Person is a series of interviews with the first authors of a selection of papers published in Disease Models & Mechanisms, helping early-career researchers promote themselves alongside their papers. Geon Seong Lee is first author on ‘ Morc2a p.S87L mutant mice develop peripheral and central neuropathies associated with neuronal DNA damage and apoptosis ’, published in DMM. Geon Seong is a PhD student in the lab of Su Cheong Yeom at Seoul National University, Pyeongchang, South Korea, investigating gene-editing therapy for single-nucleotide polymorphism-mediated genetic disorder.…”