Characterization of molecular mechanisms underlying the axonal Charcot–Marie–Tooth neuropathy caused by MORC2 mutations

Sancho, Paula; Bartesaghi, Luca; Miossec, Olivia; García‐García, Francisco; Ramírez‐Jiménez, Laura; Siddell, Anna; Åkesson, Elisabet; Hedlund, Eva; Laššuthová, Petra; Pascual, Pascual; Sevilla, Teresa; Kennerson, Marina; Lupo, Vincenzo; Chrast, Roman; Espinós, Carmen

doi:10.1093/hmg/ddz006

Cited by 35 publications

(46 citation statements)

References 49 publications

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“…The presence of hearing loss and pigmentary retinopathy further suggested the diagnosis of a mitochondrial disorder. MORC2 is involved in epigenetic silencing and expressed in neural tissues predominantly at early stages of development, 2,19 providing a potential substrate for neurodevelopmental disability. MORC2 has also been shown to bind ATP citrate lyase, the enzyme that catalyzes the formation of cytosolic acetyl-CoA, a critical building block for multiple biosynthetic pathways, 20 providing a potential mechanism for the presence of mitochondrial features in these individuals.…”

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confidence: 99%

De Novo Variants in the ATPase Module of MORC2 Cause a Neurodevelopmental Disorder with Growth Retardation and Variable Craniofacial Dysmorphism

Sacoto¹,

Tchasovnikarova

Torti³

et al. 2020

The American Journal of Human Genetics

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MORC2 encodes an ATPase that plays a role in chromatin remodeling, DNA repair, and transcriptional regulation. Heterozygous variants in MORC2 have been reported in individuals with autosomal-dominant Charcot-Marie-Tooth disease type 2Z and spinal muscular atrophy, and the onset of symptoms ranges from infancy to the second decade of life. Here, we present a cohort of 20 individuals referred for exome sequencing who harbor pathogenic variants in the ATPase module of MORC2. Individuals presented with a similar phenotype consisting of developmental delay, intellectual disability, growth retardation, microcephaly, and variable craniofacial dysmorphism. Weakness, hyporeflexia, and electrophysiologic abnormalities suggestive of neuropathy were frequently observed but were not the predominant feature. Five of 18 individuals for whom brain imaging was available had lesions reminiscent of those observed in Leigh syndrome, and five of six individuals who had dilated eye exams had retinal pigmentary abnormalities. Functional assays revealed that these MORC2 variants result in hyperactivation of epigenetic silencing by the HUSH complex, supporting their pathogenicity. The described set of morphological, growth, developmental, and neurological findings and medical concerns expands the spectrum of genetic disorders resulting from pathogenic variants in MORC2.Microrchidia CW-type zinc finger protein 2 (MORC2, MIM: 616661) is a member of a family of ATPases fundamental for epigenetic silencing through chromatin modification. [1][2][3] It has most commonly been associated with autosomal-dominant Charcot-Marie-Tooth (CMT) disease type 2Z (MIM: 616688), a form of axonal neuropathy with progressive weakness, muscle cramps, and sensory impair-ment presenting in childhood or early adulthood. [4][5][6][7] However, some reported individuals presented with hypotonia, generalized muscle weakness, and delayed milestones, 4 or occasionally with spinal muscular atrophy, intellectual disability, hearing loss, pyramidal signs, microcephaly, and brain atrophy, in infancy. 4,5,[8][9][10] The association of MORC2 variants with human disease has only recently

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confidence: 99%

De Novo Variants in the ATPase Module of MORC2 Cause a Neurodevelopmental Disorder with Growth Retardation and Variable Craniofacial Dysmorphism

Sacoto¹,

Tchasovnikarova

Torti³

et al. 2020

The American Journal of Human Genetics

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“…Recent studies highlight the use of microtubule stabilizing agents as potential drugs for improving axonal transport and therefore nerve function in these diseases [40]. Noteworthy, the pathogenesis of CMT2Z caused by mutations in MORC2 gene could be also linked to disturbances in trafficking along microtubules [41]. Beta-tubulin is known to interact with GDAP1 [14,15], therefore changes in the interaction between beta-tubulin and GDAP1, caused by mutations in GDAP1, could impact microtubules and subsequently TGN structure and function.…”

Section: Discussionmentioning

confidence: 99%

Mutations in GDAP1 Influence Structure and Function of the Trans-Golgi Network

Binięda

Rzepnikowska

Kolakowski

et al. 2021

IJMS

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Charcot-Marie-Tooth disease (CMT) is a heritable neurodegenerative disease that displays great genetic heterogeneity. The genes and mutations that underlie this heterogeneity have been extensively characterized by molecular genetics. However, the molecular pathogenesis of the vast majority of CMT subtypes remains terra incognita. Any attempts to perform experimental therapy for CMT disease are limited by a lack of understanding of the pathogenesis at a molecular level. In this study, we aim to identify the molecular pathways that are disturbed by mutations in the gene encoding GDAP1 using both yeast and human cell, based models of CMT-GDAP1 disease. We found that some mutations in GDAP1 led to a reduced expression of the GDAP1 protein and resulted in a selective disruption of the Golgi apparatus. These structural alterations are accompanied by functional disturbances within the Golgi. We screened over 1500 drugs that are available on the market using our yeast-based CMT-GDAP1 model. Drugs were identified that had both positive and negative effects on cell phenotypes. To the best of our knowledge, this study is the first report of the Golgi apparatus playing a role in the pathology of CMT disorders. The drugs we identified, using our yeast-based CMT-GDAP1 model, may be further used in translational research.

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“…Our report confirmed that patients carrying the p.S87L or p.T424R mutation shared a similar phenotype of SMA-like disease with complex syndrome. Sancho observed that the p.S87L mutation of MORC2 led to an increase in axonal swelling in neurons, which represented abnormal accumulation of axonal cargos and cytoskeletal proteins, directly affected the axonal transport systems through microtubules and motor proteins [ 24 ]. As a hallmark of axonal injury, axonal swelling underlie the pathogenesis of the neuropathy and contribute to disease severity and progression.…”

Section: Discussionmentioning

confidence: 99%

Characterization of genotype–phenotype correlation with MORC2 mutated Axonal Charcot–Marie–Tooth disease in a cohort of Chinese patients

Duan

Liu

Wang

et al. 2021

Orphanet J Rare Dis

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Background Charcot–Marie–Tooth (CMT) disease is an exciting field of study, with a growing number of causal genes and an expanding phenotypic spectrum. The microrchidia family CW-type zinc finger 2 gene (MORC2) was newly identified as a causative gene of CMT2Z in 2016. We aimed to describe the phenotypic-genetic spectrum of MORC2-related diseases in the Chinese population. Methods With the use of Sanger sequencing and Next Generation Sequencing (NGS) technologies, we screened a cohort of 284 unrelated Chinese CMT2 families. Pathogenicity assessments of MORC2 variants were interpreted according to the ACMG guidelines. Potential pathogenic variants were confirmed by Sanger sequencing. Results We identified 4 different heterozygous MORC2 mutations in four unrelated families, accounting for 1.4% (4/284). A novel mutation c.1397A>G p. D466G was detected in family 1 and all affected patients presented with later onset axonal CMT with hyperCKemia. The patient in family 2 showed a spinal muscular atrophy (SMA)-like disease with cerebellar hypoplasia and mental retardation, with a hot spot de novo mutation c.260C>T p. S87L. The twin sisters in family 3 were identified as having the most common mutation c.754C>T p. R252W and suffered from axonal motor neuropathy with high variability in disease severity and duration. The patient in family 4 developed an early onset axonal motor and sensory neuropathy, with a reported mutation c.1220G>A p.C407Y. All identified mutations associated with MORC2-related neuropathies are localized in the N-terminal ATPase module. Conclusions Our study confirmed that MORC2-related neuropathies exist in the Chinese population at a relatively high mutation rate. We revealed a complex genotype–phenotype correlation with MORC2 mutations. This report adds a new piece to the puzzle of the genetics of CMT and contributes to a better understanding of the disease mechanisms.

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Characterization of molecular mechanisms underlying the axonal Charcot–Marie–Tooth neuropathy caused by MORC2 mutations

Cited by 35 publications

References 49 publications

De Novo Variants in the ATPase Module of MORC2 Cause a Neurodevelopmental Disorder with Growth Retardation and Variable Craniofacial Dysmorphism

De Novo Variants in the ATPase Module of MORC2 Cause a Neurodevelopmental Disorder with Growth Retardation and Variable Craniofacial Dysmorphism

Mutations in GDAP1 Influence Structure and Function of the Trans-Golgi Network

Characterization of genotype–phenotype correlation with MORC2 mutated Axonal Charcot–Marie–Tooth disease in a cohort of Chinese patients

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