A multidimensional computational exploration of congenital myasthenic syndrome causing mutations in human choline acetyltransferase

2021 ◽  
Author(s):  
Matej Janežič ◽  
Kalarickal V. Dileep ◽  
Kam Y. J. Zhang
Keyword(s):  
Choline Acetyltransferase ◽  
Congenital Myasthenic Syndrome ◽  
Computational Exploration ◽  
Myasthenic Syndrome

scholarly journals Congenital Myasthenic Syndrome Due to Choline Acetyltransferase Mutations in Infants

2013 ◽  
Vol 29 (3) ◽  
pp. 389-393 ◽  
Author(s):  
Robertino Dilena ◽  
Angela Abicht ◽  
Paola Sergi ◽  
Giacomo P. Comi ◽  
Alessio Di Fonzo ◽  
...  
Keyword(s):  
Choline Acetyltransferase ◽  
Congenital Myasthenic Syndrome ◽  
Myasthenic Syndrome

scholarly journals Function of Neuromuscular Synapses in the Zebrafish Choline-Acetyltransferase Mutant bajan

2008 ◽  
Vol 100 (4) ◽  
pp. 1995-2004 ◽  
Author(s):  
Meng Wang ◽  
Hua Wen ◽  
Paul Brehm
Keyword(s):  
Choline Acetyltransferase ◽  
Residual Activity ◽  
Direct Consequence ◽  
Synaptic Function ◽  
Congenital Myasthenic Syndrome ◽  
Quantal Content ◽  
Quantal Size ◽  
Gene Coding ◽  
Myasthenic Syndrome ◽  
The Impact

We have identified a zebrafish mutant line, bajan, in which compromised motility and fatigue result from a point mutation in the gene coding choline acetyltransferase (ChAT), the enzyme responsible for acetylcholine (ACh) synthesis. Although the mutation predicts loss of ChAT function, bajan inexplicably retains low levels of neuromuscular transmission. We exploited this residual activity and determined the consequences for synaptic function. The attenuated synaptic responses were a direct consequence of a decrease in both resting mean quantal size and quantal content. To replicate behavioral fatigue in swimming, motorneurons were stimulated at high frequencies. A prominent reduction in quantal content, reflecting vesicle depletion, was coincident with a small additional reduction in quantal size. In humans, defective ChAT leads to episodic apnea, a form of congenital myasthenic syndrome characterized by use-dependent fatigue. In contrast to bajan, however, afflicted individuals exhibit a normal resting quantal size and quantal content. The fatigue in humans results from a pronounced long-lasting drop in quantal size with little or no change in quantal content. These differences have important implications for interpreting fatigue as well as on understanding the impact of ACh availability on vesicle filling and recycling.

Congenital myasthenic syndrome due to a novel missense mutation in the gene encoding choline acetyltransferase

2003 ◽  
Vol 13 (3) ◽  
pp. 245-251 ◽  
Author(s):  
Carolin Schmidt ◽  
Angela Abicht ◽  
Klaus Krampfl ◽  
Wolfgang Voss ◽  
Rolf Stucka ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Choline Acetyltransferase ◽  
Congenital Myasthenic Syndrome ◽  
Gene Encoding ◽  
Myasthenic Syndrome

scholarly journals Protein Kinase C Isoforms Differentially Phosphorylate Human Choline Acetyltransferase Regulating Its Catalytic Activity

2004 ◽  
Vol 279 (50) ◽  
pp. 52059-52068 ◽  
Author(s):  
Tomas Dobransky ◽  
Amanda Doherty-Kirby ◽  
Ae-Ri Kim ◽  
Dyanne Brewer ◽  
Gilles Lajoie ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Choline Acetyltransferase ◽  
Cholinergic Neurons ◽  
Congenital Myasthenic Syndrome ◽  
Chat Activity ◽  
Kinase C ◽  
Pkc Isoforms ◽  
Myasthenic Syndrome ◽  
Pkc Activation

Choline acetyltransferase (ChAT) synthesizes acetylcholine in cholinergic neurons; regulation of its activity or response to physiological stimuli is poorly understood. We show that ChAT is differentially phosphorylated by protein kinase C (PKC) isoforms on four serines (Ser-440, Ser-346, Ser-347, and Ser-476) and one threonine (Thr-255). This phosphorylation is hierarchical, with phosphorylation at Ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation. Ser-476 with Ser-440 and Ser-346/347 maintains basal ChAT activity. Ser-440 is targeted by Arg-442 for phosphorylation by PKC. Arg-442 is mutated spontaneously (R442H) in congenital myasthenic syndrome, rendering ChAT inactive and causing neuromuscular failure. This mutation eliminates phosphorylation of Ser-440, and Arg-442, not phosphorylation of Ser-440, appears primarily responsible for ChAT activity, with Ser-440 phosphorylation modulating catalysis. Finally, basal ChAT phosphorylation in neurons is mediated predominantly by PKC at Ser-476, with PKC activation increasing phosphorylation at Ser-440 and enhancing ChAT activity.

scholarly journals Choline Acetyltransferase Mutations Causing Congenital Myasthenic Syndrome: Molecular Findings and Genotype-Phenotype Correlations

2015 ◽  
Vol 36 (9) ◽  
pp. 881-893 ◽  
Author(s):  
Juan Arredondo ◽  
Marian Lara ◽  
Sídney M. Gospe ◽  
Claudio G. Mazia ◽  
Maria Vaccarezza ◽  
...  
Keyword(s):  
Choline Acetyltransferase ◽  
Congenital Myasthenic Syndrome ◽  
Myasthenic Syndrome

scholarly journals COVID-19 in a Cohort of Patients with Congenital Myasthenic Syndrome

2021 ◽  
pp. 1-3
Author(s):  
Setareh Alabaf ◽  
Karen O'Connell ◽  
Sithara Ramdas ◽  
David Beeson ◽  
Jacqueline Palace
Keyword(s):  
High Risk ◽  
Neuromuscular Transmission ◽  
Genetic Disorders ◽  
Severe Disease ◽  
Congenital Myasthenic Syndrome ◽  
Referral Centre ◽  
History Of ◽  
Myasthenic Syndrome ◽  
The Uk ◽  
Rare Group

Congenital Myasthenic Syndrome (CMS) are a rare group of genetic disorders of neuromuscular transmission. Some subtypes of CMS can be associated with respiratory and bulbar weakness and these patients may therefore be at high risk of developing a severe disease from COVID-19. We screened 73 patients with genetically confirmed CMS who were attending the UK national referral centre for evidence of previous Severe Acute Respiratory Syndrome Corona Virus 2 infection and their clinical outcome. Of 73 patients, seven had history of confirmed COVID-19. None of the infected patients developed a severe disease, and there were no signals that CMS alone carries a high risk of severe disease from COVID-19.

Combined Muscle Biopsy and Comprehensive Electrophysiology in General Anesthesia is Valuable in Diagnosis of Neuromuscular Disease in Children

2021 ◽  
Author(s):  
Christina E. Hoei-Hansen ◽  
Marie L. B. Tygesen ◽  
Morten Dunø ◽  
John Vissing ◽  
Martin Ballegaard ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Muscle Biopsy ◽  
Neuromuscular Disease ◽  
Genetic Diagnosis ◽  
Congenital Myasthenic Syndrome ◽  
Diagnostic Quality ◽  
Pathogenic Variants ◽  
Combined Use ◽  
Myasthenic Syndrome ◽  
Size Variability

Abstract Aim The diagnostic workup in patients with delayed motor milestones suspected of having either myopathy or a congenital myasthenic syndrome is complex. Our hypothesis was that performance of a muscle biopsy and neurophysiology including stimulated single-fiber electromyography during an anesthetic procedure, combined with genetic testing has a high diagnostic quality. Materials and Methods Clinical and paraclinical data were retrospectively collected from 24 patients aged from 1 month to 10 years (median: 5.2 years). Results Neurophysiology examination was performed in all patients and was abnormal in 11 of 24. No patients had findings suggestive of a myasthenic syndrome. Muscle biopsy was performed in 21 of 24 and was normal in 16. Diagnostic findings included nemaline rods, inclusion bodies, fiber size variability, and type-II fiber atrophy. Genetic testing with either a gene panel or exome sequencing was performed in 18 of 24 patients, with pathogenic variants detected in ACTA1, NEB, SELENON, GRIN2B, SCN8A, and COMP genes. Conclusion Results supporting a neuromuscular abnormality were found in 15 of 24. In six patients (25%), we confirmed a genetic diagnosis and 12 had a clinical neuromuscular diagnosis. The study suggests that combined use of neurophysiology and muscle biopsy in cases where genetic testing does not provide a diagnosis can be useful in children with delayed motor milestones and clinical evidence of a neuromuscular disease.

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