Recessive VAMP1 mutations associated with severe congenital myasthenic syndromes – A recognizable clinical phenotype

Polavarapu, Kiran; Vengalil, Seena; Preethish‐Kumar, Veeramani; Arunachal, Gautham; Nashi, Saraswati; Mohan, Dhaarini; Chawla, Tanushree; Bardhan, Mainak; Nandeesh, Bevinahalli N; Gupta, Priya; Gowda, Vykuntaraju K; Lochmüller, Hanns; Nalini, Atchayaram

doi:10.1016/j.ejpn.2021.02.005

Cited by 9 publications

(18 citation statements)

References 17 publications

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“…VAMP1, a member of the synaptobrevin family, is involved in synaptic vesicle docking and fusion. [ 49 ] VAMP1 is also a core component of the SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptors) complex that mediates intracellular vesicular trafficking. [ 50 ] VAMP1 acts as a v-SNARE and interacts with SNAP-25 and syntaxin1 to form a stable complex for vesicular fusion and neurotransmitter release.…”

Section: Discussionmentioning

confidence: 99%

Dexmedetomidine Mitigates Microglial Activation Associated with Postoperative Cognitive Dysfunction by Modulating the MicroRNA-103a-3p/VAMP1 Axis

Wang

Shi

et al. 2022

Neural Plasticity

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Surgery-induced microglial activation is critical in mediating postoperative cognitive dysfunction (POCD) in elderly patients, where the important protective effect of dexmedetomidine has been indicated. However, the mechanisms of action of dexmedetomidine during the neuroinflammatory response that underlies POCD remain largely unknown. We found that lipopolysaccharide (LPS) induced substantial inflammatory responses in primary and BV2 microglial cells. The screening of differentially expressed miRNAs revealed that miR-103a-3p was downregulated in these cell culture models. Overexpression of miR-103a-3p mimics and inhibitors suppressed and enhanced the release of inflammatory factors, respectively. VAMP1 expression was upregulated in LPS-treated primary and BV-2 microglial cells, and it was validated as a downstream target of miR-103-3p. VAMP1-knockdown significantly inhibited the LPS-induced inflammatory response. Dexmedetomidine treatment markedly inhibited LPS-induced inflammation and the expression of VAMP1, and miR-103a-3p expression reversed this inhibition. Moreover, dexmedetomidine mitigated microglial activation and the associated inflammatory response in a rat model of surgical trauma that mimicked POCD. In this model, dexmedetomidine reversed miR-103a-3p and VAMP1 expression; this effect was abolished by miR-103a-3p overexpression. Taken together, the data show that miR-103a-3p/VAMP1 is critical for surgery-induced microglial activation of POCD.

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Section: Discussionmentioning

confidence: 99%

Dexmedetomidine Mitigates Microglial Activation Associated with Postoperative Cognitive Dysfunction by Modulating the MicroRNA-103a-3p/VAMP1 Axis

Wang

Shi

et al. 2022

Neural Plasticity

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“…Biallelic loss-of-function variant of VAMP1 encoding another component of the SNARE complex, synaptobrevin1, cause a neonatal onset CMS [ 379 , 380 , 381 ]. Vamp1 -deficient mice showed marked shrinkage of motor endplate and reduction in endplate potentials, which is electrophysiologically similar to LEMS [ 379 ].…”

Section: Thirty-five Genes In 14 Groups Of Cmsmentioning

confidence: 99%

Section: Thirty-five Genes In 14 Groups Of Cmsmentioning

confidence: 99%

“…VAMP1 -CMS has been reported in 9 patients in 7 pedigrees since 2017 [ 10 , 379 , 380 , 381 ]. Patients had muscle hypotonia, muscle weakness, and myasthenia since birth [ 10 , 379 , 381 ] or age 6 months [ 380 ]. CMAPs decremented and incremented in response to low- and high-frequency RNS, respectively [ 10 , 379 ].…”

Section: Thirty-five Genes In 14 Groups Of Cmsmentioning

confidence: 99%

“…CMAPs decremented and incremented in response to low- and high-frequency RNS, respectively [ 10 , 379 ]. External ophthalmoplegia and bulbar palsy were also noted [ 10 , 379 , 381 ]. ChEIs were effective for VAMP1 -CMS [ 10 , 379 , 380 , 381 ].…”

Section: Thirty-five Genes In 14 Groups Of Cmsmentioning

confidence: 99%

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Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes—A Comprehensive Review

Ohno

Ohkawara

Shen

et al. 2023

IJMS

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Congenital myasthenic syndromes (CMS) are a heterogeneous group of disorders characterized by impaired neuromuscular signal transmission due to germline pathogenic variants in genes expressed at the neuromuscular junction (NMJ). A total of 35 genes have been reported in CMS (AGRN, ALG14, ALG2, CHAT, CHD8, CHRNA1, CHRNB1, CHRND, CHRNE, CHRNG, COL13A1, COLQ, DOK7, DPAGT1, GFPT1, GMPPB, LAMA5, LAMB2, LRP4, MUSK, MYO9A, PLEC, PREPL, PURA, RAPSN, RPH3A, SCN4A, SLC18A3, SLC25A1, SLC5A7, SNAP25, SYT2, TOR1AIP1, UNC13A, VAMP1). The 35 genes can be classified into 14 groups according to the pathomechanical, clinical, and therapeutic features of CMS patients. Measurement of compound muscle action potentials elicited by repetitive nerve stimulation is required to diagnose CMS. Clinical and electrophysiological features are not sufficient to identify a defective molecule, and genetic studies are always required for accurate diagnosis. From a pharmacological point of view, cholinesterase inhibitors are effective in most groups of CMS, but are contraindicated in some groups of CMS. Similarly, ephedrine, salbutamol (albuterol), amifampridine are effective in most but not all groups of CMS. This review extensively covers pathomechanical and clinical features of CMS by citing 442 relevant articles.

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Advancing the Understanding of Vesicle-Associated Membrane Protein 1-Related Congenital Myasthenic Syndrome: Phenotypic Insights, Favorable Response to 3,4-Diaminopyridine, and Clinical Characterization of Five New Cases

Natera-de Benito,

Pugliese,

Polavarapu

et al. 2024

Pediatric Neurology

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Recessive VAMP1 mutations associated with severe congenital myasthenic syndromes – A recognizable clinical phenotype

Cited by 9 publications

References 17 publications

Dexmedetomidine Mitigates Microglial Activation Associated with Postoperative Cognitive Dysfunction by Modulating the MicroRNA-103a-3p/VAMP1 Axis

Dexmedetomidine Mitigates Microglial Activation Associated with Postoperative Cognitive Dysfunction by Modulating the MicroRNA-103a-3p/VAMP1 Axis

Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes—A Comprehensive Review

Advancing the Understanding of Vesicle-Associated Membrane Protein 1-Related Congenital Myasthenic Syndrome: Phenotypic Insights, Favorable Response to 3,4-Diaminopyridine, and Clinical Characterization of Five New Cases

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