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Article dans une revue

Impaired Presynaptic High-Affinity Choline Transporter Causes a Congenital Myasthenic Syndrome with Episodic Apnea

Stéphanie Bauché 1 Seana O’regan Yoshiteru Azuma 2 Fanny Laffargue 3 Grace Mcmacken Damien Sternberg 4 Guy Brochier 5 Céline Buon Nassima Bouzidi Ana Topf Emmanuelle Lacène 6 Ganaelle Remerand Anne Beaufrere Céline Pebrel-Richard Julien Thévenon 7 Salima El chehadeh-Djebbar Laure Faivre 8 Yannis Duffourd 8 Federica Ricci Tiziana Mongini Chiara Fiorillo Guja Astrea Carmen Burloiu Niculina Butoianu Carmen Sandu Laure Servais Gisèle Bonne 9 Isabelle Nelson 10 Isabelle Desguerre 11 Marie-Christine Nougues Benoit Bœuf Norma Romero 6 Jocelyn Laporte 12 Anne Boland 13 Doris Lechner 13 Jean-François Deleuze 13 Bertrand Fontaine 14 Laure Strochlic 15 Hanns Lochmuller 2 Bruno Eymard 1 Michèle Mayer 16 Sophie Nicole 1, *
* Auteur correspondant
1 ICM - Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute
2 Newcastle University [Newcastle]
3 Service de Génétique Médical
4 CHU Pitié-Salpêtrière [AP-HP]
5 Unité de Morphologie Neuromusculaire
6 Institut de Myologie
7 Biologie moléculaire et cellulaire de la différenciation
8 Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon)
9 Thérapie des maladies du muscle strié
10 Centre de recherche en myologie
11 IMRB - Institut Mondor de recherche biomédicale
12 IGBMC - Institut de génétique et biologie moléculaire et cellulaire
13 CNG - Centre National de Génotypage
14 Albert Einstein College of Medicine [New York]
15 IJM (UMR_7592) - Institut Jacques Monod
16 Service de neurologie pédiatriques et maladies du dévéloppement
Abstract : The neuromuscular junction (NMJ) is one of the best-studied cholinergic synapses. Inherited defects of peripheral neurotransmission result in congenital myasthenic syndromes (CMS5), a clinically and genetically heterogeneous group of rare diseases with fluctuating fatigable muscle weakness as the clinical hallmark. Whole-exome sequencing and Sanger sequencing in six unrelated families identified compound heterozygous and homozygous mutations in SLC5A7 encoding the presynaptic sodium-dependent high-affinity choline transporter 1 (CHT), which is known to be mutated in one dominant form of distal motor neuronopathy (DHMN7A). We identified 11 recessive mutations in SLC5A7 that were associated with a spectrum of severe muscle weakness ranging from a lethal antenatal form of arthrogryposis and severe hypotonia to a neonatal form of CMS with episodic apnea and a favorable prognosis when well managed at the clinical level. As expected given the critical role of CHT for multisystemic cholinergic neurotransmission, autonomic dysfunctions were reported in the antenatal form and cognitive impairment was noticed in half of the persons with the neonatal form. The missense mutations induced a near complete loss of function of CHT activity in cell models. At the human NMJ, a delay in synaptic maturation and an altered maintenance were observed in the antenatal and neonatal forms, respectively. Increased synaptic expression of butyrylcholinesterase was also observed, exposing the dysfunction of cholinergic metabolism when CHT is deficient in vivo. This work broadens the clinical spectrum of human diseases resulting from reduced CHT activity and highlights the complexity of cholinergic metabolism at the synapse.
Keywords : neuromuscular-junction respiratory rhythm knockout mouse butyrylcholinesterase mutations receptors acetyltransferase neurotransmission deficiency expression
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https://hal-univ-bourgogne.archives-ouvertes.fr/hal-01680226
Contributeur : Gad - Université de Bourgogne <>
Soumis le : mercredi 10 janvier 2018 - 14:33:53
Dernière modification le : vendredi 25 septembre 2020 - 15:30:04

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UNIV-BOURGOGNE | CNRS | UNIV-PARIS7 | IGBMC | U823 | UPMC | IMRB | IJM | UPEC-UPEM | CEA | ICM | U974 | UGA | USPC | JACOB | CEA-DRF | SORBONNE-UNIVERSITE | SU-MEDECINE | UPEC | SITE-ALSACE | UNIV-PARIS | UP-SCIENCES

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Stéphanie Bauché, Seana O’regan, Yoshiteru Azuma, Fanny Laffargue, Grace Mcmacken, et al.. Impaired Presynaptic High-Affinity Choline Transporter Causes a Congenital Myasthenic Syndrome with Episodic Apnea. American Journal of Human Genetics, Elsevier (Cell Press), 2016, 99 (3), pp.753 - 761. ⟨10.1016/j.ajhg.2016.06.033⟩. ⟨hal-01680226⟩

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