Trk receptor signalling and sensory neuron fate are perturbed in human neuropathy caused by Gars mutations

Sleigh, James N.; Dawes, J. D. K.; West, Steven J.; Wei, Na; Spaulding, Emily L.; Gómez-Martín, A; Zhang, Q.; Burgess, Robert W.; Cader, M Z; Talbot, Konrad; Yang, Xiaoyun; Bennett, Deborah L.; Schiavo, Giampietro

doi:10.1016/s0960-8966(17)30294-8

Cited by 5 publications

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“…The adolescent onset and the presence of sensory symptoms in the patients indicate that they present CMT2D rather than dSMA‐V. The underlying mechanism distinguishing CMT2D from its allelic disease dSMA‐V is still not well elucidated although a recent study has suggested that CMT2D pathogenesis involves both neurodevelopmental and neurodegenerative processes (Sleigh et al, ).…”

Section: Discussionmentioning

confidence: 99%

A novel mutation in the GARS gene in a Malian family with Charcot‐Marie‐Tooth disease

Yalcouyé

Diallo

Coulibaly

et al. 2019

Molec Gen & Gen Med

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Background Charcot‐Marie‐Tooth (CMT) disease is a very heterogeneous neurological condition with more than 90 reported genetic entities. It is the most common inherited peripheral neuropathy; however, cases are rarely reported in sub‐Saharan Africa. In addition, only few families, mostly of Caucasian ancestry, have been reported to have Charcot‐Marie‐Tooth disease type 2D (CMT2D) mutations. To date no case of CMT2D was reported in Africa. We present here a consanguineous family with CMT phenotype in which a novel mutation in the GARS (glycyl‐tRNA synthetase) gene was identified. Methods Patients were examined thoroughly and nerve conduction studies (NCS) were performed. DNA from the proband was used for CMT gene panel testing (including 50 genes, PMP22 duplication and mtDNA ). Putative mutations were verified in all available family members to check for segregation. Results Two individuals, a male and a female, were found to be affected. Symptoms started in their teenage years with muscle weakness and atrophy in hands. Later, distal involvement of the lower limbs was noticed. Patients complained of minor sensory impairment. NCS showed no response in the upper as well as the lower limbs. Genetic testing surprisingly identified a novel heterozygous missense mutation c.794C>A (p.Ser265Tyr) in the GARS gene associated with CMT2D. This variant segregated with the disease in the family and was also seen in the mother who presented no symptoms. Conclusion This is the first report of a genetically confirmed CMT2D case in Africa, expanding its genetic epidemiology. Increasing access to genetic testing may reveal more novel CMT variants or genes in the African population that could be relevant to other populations and further our understanding of their mechanism.

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Section: Discussionmentioning

confidence: 99%

A novel mutation in the GARS gene in a Malian family with Charcot‐Marie‐Tooth disease

Yalcouyé

Diallo

Coulibaly

et al. 2019

Molec Gen & Gen Med

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“…This pathway was also linked to developmental cardiovascular defects and vascular homeostasis which was not observed in Gars mouse models . Furthermore, abnormal interference of mutant GARS with Trk receptors has been shown to have a role in the development of sensory neurons . Exploration of the interacting partners of several mutant ARS variants may shed light on a common pathological mechanism explaining the neuromuscular phenotype.…”

Section: Gain‐of‐function Through Neomorphic Bindingmentioning

confidence: 99%

The role of tRNA synthetases in neurological and neuromuscular disorders

2018

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Aminoacyl‐tRNA synthetases (ARSs) are ubiquitously expressed enzymes responsible for charging tRNAs with their cognate amino acids, therefore essential for the first step in protein synthesis. Although the majority of protein synthesis happens in the cytosol, an additional translation apparatus is required to translate the 13 mitochondrial DNA‐encoded proteins important for oxidative phosphorylation. Most ARS genes in these cellular compartments are distinct, but two genes are common, encoding aminoacyl‐tRNA synthetases of glycine (GARS) and lysine (KARS) in both mitochondria and the cytosol. Mutations in the majority of the 37 nuclear‐encoded human ARS genes have been linked to a variety of recessive and dominant tissue‐specific disorders. Current data indicate that impaired enzyme function could explain the pathogenicity, however not all pathogenic ARSs mutations result in deficient catalytic function; thus, the consequences of mutations may arise from other molecular mechanisms. The peripheral nerves are frequently affected, as illustrated by the high number of mutations in cytosolic and bifunctional tRNA synthetases causing Charcot–Marie–Tooth disease (CMT). Here we provide insights on the pathomechanisms of CMT‐causing tRNA synthetases with specific focus on the two bifunctional tRNA synthetases (GARS, KARS).

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“…In the present study, we first identified that within DRG neurons with a diameter of 15-45 μm IL-6 co-localized with peripherin (Figure 2a), a marker to label the small diameter of neurons supplying thinly unmyelinated C-fibers (Saveri et al, 2020;Sleigh et al, 2017). In addition, we found that the protein levels of both IL-6 and IL-6R were increased in the DRGs of PAD rats after femoral artery was occluded for 3 days (Figure 2b,c).…”

Section: Discussionmentioning

confidence: 59%

IL‐6 signaling pathway contributes to exercise pressor reflex in rats with femoral artery occlusion in association with Kv4 activity in muscle afferent nerves

Trk receptor signalling and sensory neuron fate are perturbed in human neuropathy caused by Gars mutations

Cited by 5 publications

References 0 publications

A novel mutation in the GARS gene in a Malian family with Charcot‐Marie‐Tooth disease

A novel mutation in the GARS gene in a Malian family with Charcot‐Marie‐Tooth disease

The role of tRNA synthetases in neurological and neuromuscular disorders

IL‐6 signaling pathway contributes to exercise pressor reflex in rats with femoral artery occlusion in association with Kv4 activity in muscle afferent nerves

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