One Multilocus Genomic Variation Is Responsible for a Severe Charcot–Marie–Tooth Axonal Form

Miressi, Federica; Magdelaine, Corinne; Pascal, Pierre; Bourthoumieux, Sylvie; Nizou, Angélique; Derouault, Paco; Favreau, Fréderic; Sturtz, Franck; Faye, Pierre-Antoine; Lia, Anne‐Sophie

doi:10.3390/brainsci10120986

Cited by 5 publications

(6 citation statements)

References 26 publications

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“…This could explain the dysregulation of some genes in favor of others, explaining the development of a particular phenotype. Moreover, CMT2Z disease may be part of multilocus genetic pathologies (Miressi et al, 2020). In this study, the authors demonstrated that a combination of multiple genomic mutations is responsible for various severities in intra-familial members.…”

Section: Given Mutations Can Induce Different Phenotypesmentioning

confidence: 78%

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

Jacquier

Roubille

Lomonte

et al. 2022

Front. Cell. Neurosci.

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Microrchidia CW-type zinc finger 2 (MORC2) gene encodes a protein expressed in all tissues and enriched in the brain. MORC2 protein is composed of a catalytic ATPase domain, three coil-coiled domains allowing dimerization or protein complex interaction, a zinc-finger CW domain allowing DNA interaction, and a CHROMO-like (CHRromatin Organization Modifier) domain. Recently, de novo or dominantly inherited heterozygous mutations have been associated with a spectrum of disorders affecting the peripheral nervous system such as the Charcot-Marie-Tooth disease, spinal muscular atrophy-like phenotype disorder, or a neurodevelopmental syndrome associated with developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy (DIGFAN). In this review, we detail the various mutations of MORC2 and their consequences on clinical manifestations. Possible genotype-phenotype correlations as well as intra and inter-family variability are discussed. MORC2 molecular functions such as transcriptional modulation, DNA damage repair, and lipid metabolism are then reviewed. We further discuss the impact of MORC2 mutations on the epigenetic landscape in the neuromuscular system and hypothesize probable pathophysiological mechanisms underlying the phenotypic variability observed.

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Section: Given Mutations Can Induce Different Phenotypesmentioning

confidence: 78%

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

Jacquier

Roubille

Lomonte

et al. 2022

Front. Cell. Neurosci.

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“…This approach is already in place for other rare mendelian diseases such as Charcot-Marie-Tooth disease and others. [42][43][44][45]…”

Section: Discussionmentioning

confidence: 99%

“…A genome wide screen in ARSACS patients, aggregated based on phenotypic similarities, may provide a more complete genetic view of the disease. This approach is already in place for other rare Mendelian diseases, such as CMTs and others [42][43][44][45]. .…”

mentioning

confidence: 99%

Assessment of Sacsin Turnover in Patients With ARSACS

et al. 2021

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Background and Objectives:Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is caused by mutations in SACS gene encoding sacsin, a huge multimodular protein of unknown function. More than 200 SACS mutations have been described worldwide to date. Since ARSACS presents phenotypic variability, previous empirical studies attempted to correlate the nature and position of SACS mutations with the age of onset or with disease severity, though not considering the effect of the various mutations on protein stability. In this work, we studied genotype-phenotype correlation in ARSACS at a functional level.Methods:We analyzed a large set of skin fibroblasts derived from ARSACS patients, including both new and already published cases, carrying mutations of different type affecting diverse domains of the protein.Results:We found that sacsin is almost absent in ARSACS patients, regardless of the nature of the mutation. As expected, we did not detect sacsin in patients with truncating mutations. Interestingly, we found it strikingly reduced or absent also in compound heterozygotes carrying diverse missense mutations. In this case, we excluded SACS mRNA decay, defective translation or faster post-translational degradation as possible causes of protein reduction. Conversely, our results demonstrate that nascent mutant sacsin protein undergoes cotranslational ubiquitination and degradation.Discussion:Our results provide one mechanistic explanation for the lack of genotype-phenotype correlation in ARSACS. We also propose a new and unambiguous criterion for ARSACS diagnosis, that is based on the evaluation of sacsin level. Finally, we identified preemptive degradation of a mutant protein as a novel cause of a human disease.

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“…Meanwhile, combinations of multiple variants are rarely described. Nevertheless, in a family with CMT, the conditions of the mother and daughter were characterized by axonal damage, and were associated with MORC21, MFN2, and AARS1 variants [ 44 ]. MFN2 is a member of the mitochondrial transmembrane protein family, which is widely expressed by eukaryotic cells and plays an important role in mitochondrial fusion and division-controlled mitochondrial dynamic remodelling [ 45 ].…”

Section: Application Of Next-generation Sequencing In Neurogenetic Diseasesmentioning

confidence: 99%

“…MORC2, in combination with the MFN2 variant, result in more severe phenotypes and complex clinical symptoms. The AARS1 variant was also found in healthy members of the family, suggesting it was not an independent risk factor [ 44 ]. However, the authors were unable to conclusively determine whether the AARS1 variant worsens CMT based on the presence of other causal mutations.…”

Section: Application Of Next-generation Sequencing In Neurogenetic Diseasesmentioning

confidence: 99%

Next-Generation Sequencing Technologies and Neurogenetic Diseases

Sun

Shen

Fang

et al. 2021

Life

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Next-generation sequencing (NGS) technology has led to great advances in understanding the causes of Mendelian and complex neurological diseases. Owing to the complexity of genetic diseases, the genetic factors contributing to many rare and common neurological diseases remain poorly understood. Selecting the correct genetic test based on cost-effectiveness, coverage area, and sequencing range can improve diagnosis, treatments, and prevention. Whole-exome sequencing and whole-genome sequencing are suitable methods for finding new mutations, and gene panels are suitable for exploring the roles of specific genes in neurogenetic diseases. Here, we provide an overview of the classifications, applications, advantages, and limitations of NGS in research on neurological diseases. We further provide examples of NGS-based explorations and insights of the genetic causes of neurogenetic diseases, including Charcot–Marie–Tooth disease, spinocerebellar ataxias, epilepsy, and multiple sclerosis. In addition, we focus on issues related to NGS-based analyses, including interpretations of variants of uncertain significance, de novo mutations, congenital genetic diseases with complex phenotypes, and single-molecule real-time approaches.

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One Multilocus Genomic Variation Is Responsible for a Severe Charcot–Marie–Tooth Axonal Form

Cited by 5 publications

References 26 publications

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

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

Assessment of Sacsin Turnover in Patients With ARSACS

Next-Generation Sequencing Technologies and Neurogenetic Diseases

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