New MORC2 gene mutations are associated with distinctive features: from axonal neuropathy to late adult-onset spinal muscular atrophy like phenotype

Abstract

MORC2 gene encodes a ubiquitously expressed nuclear protein involved in chromatin remodeling, DNA repair, and transcriptional regulation. Heterozygous mutations in MORC2 gene have been associated with a spectrum of disorders affecting the peripheral nervous system such as Charcot-Marie-Tooth (CMT2Z), spinal muscular atrophy-like (SMA-like) with or without cerebellar involvement, and a developmental syndrome associated with impaired growth, craniofacial dysmorphism and axonal neuropathy (DIGFAN syndrome). Such variability in clinical manifestations associated with the increasing number of variants of unknown significance detected by next-generation sequencing constitutes a serious diagnostic challenge. Here we report the characterization of an in vitro model to evaluate the pathogenicity of variants of unknown significance based on MORC2 overexpression in a neuroblastoma cell line SH-EP or in cortical neurons. Likewise, we show that MORC2 mutants affect survival and trigger apoptosis over time in SH-EP cell line. Furthermore, overexpression in primary cortical neurons increases apoptotic cell death and decreases neurite outgrowth. Altogether, these approaches establish the pathogenicity of two new variants p.G444R and p.H446Q in three patients from two families. These new mutations in MORC2 gene are associated with autosomal dominant CMT and with adult late onset SMA-like phenotype, further increasing the spectrum of clinical manifestations associated with MORC2 mutations.

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

“…Along with the p.R252W mutation, which is the most frequent mutation, other mutations related to CMT2 were identified all along the GHKL-type and S5 domains (Figure 3). Mutations p.R132L (Hyun et al, 2016), p.E236G (Albulym et al, 2016), p.Y394C (Ando et al, 2017), p.A406V (Sivera et al, 2021), p.G444R (Albulym et al, 2016;Jacquier et al, 2022), p.D466N FIGURE 2 | Schematic representation of the clinical features in the spectrum of MORC2-related diseases. On one side, the late onset CMT2Z disease characterized by the peripheral axonopathy with a frequently scapuloperoneal presentation, or more rarely with a sensitive-motor polyneuropathy or a late-onset SMA presentation.…”

“…Interestingly, one patient suspected of having developed an adult-onset SMA without SMN1 mutation was finally classified as CMT2Z after the identification of p.R319H mutation in MORC2 (Karakaya et al, 2018). Recently, a second patient with a clinical presentation of late-onset SMA was identified in a French family with the heterozygous p.H446Q mutation, suggesting that genetically unsolved late-onset SMA patients should be considered for MORC2 sequencing (Jacquier et al, 2022).…”

Japanese case of Charcot–Marie–Tooth disease type 2Z with severe retinitis pigmentosa

“…6 MORC2 mutants in SH-EP cells activated caspase 3 and decreased cell survival by inducing apoptosis. 6 Thus, we considered that the MORC2 mutation might be involved in the degeneration of photoreceptors and the development of retinitis pigmentosa. The proband's son (III-1) still has good eyesight, but he might develop retinitis pigmentosa in the future, so it is necessary to monitor him carefully.…”

“…Several mechanisms, including cell death mechanisms such as apoptosis, necrosis, autophagy, endoplasmic reticulum stress, and oxidative stress, have been suggested as triggers of the death of rod photoreceptors 5 . The MORC2 gene encodes a ubiquitously expressed nuclear protein involved in chromatin remodeling, DNA repair, and transcriptional regulation 6 . MORC2 mutants in SH‐EP cells activated caspase 3 and decreased cell survival by inducing apoptosis 6 .…”

“…The MORC2 gene encodes a ubiquitously expressed nuclear protein involved in chromatin remodeling, DNA repair, and transcriptional regulation 6 . MORC2 mutants in SH‐EP cells activated caspase 3 and decreased cell survival by inducing apoptosis 6 . Thus, we considered that the MORC2 mutation might be involved in the degeneration of photoreceptors and the development of retinitis pigmentosa.…”