Charcot-Marie-tooth disease type 2A: An update on pathogenesis and therapeutic perspectives

Alberti, Claudia; Rizzo, Federica; Anastasia, Alessia; Comi, Giacomo; Corti, Stefania; Abati, Elena

doi:10.1016/j.nbd.2024.106467

Cited by 7 publications

(3 citation statements)

References 101 publications

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“… 47 In 2024, Alberti et al reported the pathogenesis and therapeutic perspectives for CMT2A. 48 The data from national CMT registry of Italy showed the disease epidemiology, clinical symptoms, genetic distribution and disease progression among CMT patients in Italy followed by recruiting CMT patients for future clinical trials. 49 Stavrou et al also showed the recent development of gene therapies and application of gene therapies as a therapeutic strategy for patients with CMTs.…”

Section: Discussionmentioning

confidence: 99%

Identification of a Novel Homozygous Mutation in MTMR2 Gene Causes Very Rare Charcot–Marie–Tooth Disease Type 4B1

Du,

Wang,

Wang

et al. 2024

TACG

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Background Charcot–Marie–Tooth disease (CMT) is a heterogeneous group of disorders involving peripheral nervous system. Charcot–Marie–Tooth disease 4B1 (CMT4B1) is a rare subtype of CMT. CMT4B1 is an axonal demyelinating polyneuropathy with an autosomal recessive mode of inheritance. Patients with CMT4B1 usually manifested with dysfunction of the motor and sensory systems which leads to gradual and progressive muscular weakness and atrophy, starting from the peroneal muscles and finally affecting the distal muscles. Germline mutations in MTMR2 gene causes CMT4B1. Material and Methods In this study, we investigated a 4-year-old Chinese boy with gradual and progressive weakness and atrophy of both proximal and distal muscles. The proband’s parents did not show any abnormalities. Whole-exome sequencing and Sanger sequencing were performed. Results Whole-exome sequencing identified a novel homozygous nonsense mutation (c.118A>T; p.Lys40*) in exon 2 of MTMR2 gene in the proband. This novel mutation leads to the formation of a truncated MTMR2 protein of 39 amino acids instead of the wild- type MTMR2 protein of 643 amino acids. This mutation is predicted to cause the complete loss of the PH-GRAM domain, phosphatase domain, coiled-coil domain, and PDZ-binding motif of the MTMR2 protein. Sanger sequencing revealed that the proband’s parents carried the mutation in a heterozygous state. This mutation was absent in 100 healthy control individuals. Conclusion This study reports the first mutation in MTMR2 associated with CMT4B1 in a Chinese population. Our study also showed the importance of whole-exome sequencing in identifying candidate genes and disease-causing variants in patients with CMT4B1.

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Section: Discussionmentioning

confidence: 99%

Identification of a Novel Homozygous Mutation in MTMR2 Gene Causes Very Rare Charcot–Marie–Tooth Disease Type 4B1

Du,

Wang,

Wang

et al. 2024

TACG

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“…[63][64][65] While these pathogenic variants can impact diverse aspects of mitochondrial biology 64 , many, including D414V, lead to increases in mitochondrial fragmentation. 49,[63][64][65] This can be attributed to reduced activity of MFN2-dependent fusion associated with these variants and a subsequent relative increase of DRP1-dependent mitochondrial fission. We predicted that pharmacologic, stress-independent activation of ISR kinases could rescue mitochondrial network morphology in patient fibroblasts expressing the disease-associated MFN2 variant D414V (MFN2 D414V ).…”

Section: Stress-independent Pharmacologic Activation Of Isr Kinases R...mentioning

confidence: 99%

“…Over 150 pathogenic variants in the pro-fusion GTPase MFN2 are causatively associated with the autosomal dominant peripheral neuropathy Charcot-Marie-Tooth Type 2A. [63][64][65] While these pathogenic variants can impact diverse aspects of mitochondrial biology 64 , many, including D414V, lead to increases in mitochondrial fragmentation. 49,[63][64][65] This can be attributed to reduced activity of MFN2-dependent fusion associated with these variants and a subsequent relative increase of DRP1-dependent mitochondrial fission.…”

Section: Stress-independent Pharmacologic Activation Of Isr Kinases R...mentioning

confidence: 99%

Pharmacologic Activation of Integrated Stress Response Kinases Inhibits Pathologic Mitochondrial Fragmentation

Baron,

Oviedo,

Krasny

et al. 2024

Preprint

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SUMMARYExcessive mitochondrial fragmentation is associated with the pathologic mitochondrial dysfunction implicated in the pathogenesis of etiologically-diverse diseases, including many neurodegenerative disorders. The integrated stress response (ISR) – comprising the four eIF2α kinases PERK, GCN2, PKR, and HRI – is a prominent stress-responsive signaling pathway that regulates mitochondrial morphology and function in response to diverse types of pathologic insult. This suggests that pharmacologic, stress-independent activation of the ISR represents a potential strategy to mitigate pathologic mitochondrial fragmentation associated with human disease. Here, we show that pharmacologic, stress-independent activation of the ISR kinases HRI or GCN2 promotes adaptive mitochondrial elongation and prevents mitochondrial fragmentation induced by the calcium ionophore ionomycin. Further, we show that stress-independent activation of these ISR kinases reduces mitochondrial fragmentation and restores basal mitochondrial morphology in patient fibroblasts expressing the pathogenic D414V variant of the pro-fusion mitochondrial GTPase MFN2 associated with neurological dysfunctions including ataxia, optic atrophy, and sensorineural hearing loss. These results identify pharmacologic, stress-independent activation of ISR kinases as a potential strategy to prevent pathologic mitochondrial fragmentation induced by disease-relevant chemical and genetic insults, further motivating the pursuit of highly selective ISR kinase-activating compounds as a therapeutic strategy to mitigate mitochondrial dysfunction implicated in diverse human diseases.

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Genetic therapies and potential therapeutic applications of CRISPR activators in the eye

Ng,

Kaukonen,

McClements

et al. 2024

Progress in Retinal and Eye Research

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Charcot-Marie-tooth disease type 2A: An update on pathogenesis and therapeutic perspectives

Cited by 7 publications

References 101 publications

Identification of a Novel Homozygous Mutation in MTMR2 Gene Causes Very Rare Charcot–Marie–Tooth Disease Type 4B1

Identification of a Novel Homozygous Mutation in MTMR2 Gene Causes Very Rare Charcot–Marie–Tooth Disease Type 4B1

Pharmacologic Activation of Integrated Stress Response Kinases Inhibits Pathologic Mitochondrial Fragmentation

Genetic therapies and potential therapeutic applications of CRISPR activators in the eye

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