Impaired Presynaptic High-Affinity Choline Transporter Causes a Congenital Myasthenic Syndrome with Episodic Apnea PMID: 27569547

ADC Targets in Oncology

2026-04-10

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

Am J Hum Genet. 2016 Sep 1;99(3):753-761. doi: 10.1016/j.ajhg.2016.06.033.

Stéphanie Bauché ¹ , Seana O'Regan ² , Yoshiteru Azuma ³ , Fanny Laffargue ⁴ , Grace McMacken ³ , Damien Sternberg ⁵ , Guy Brochier ⁶ , Céline Buon ¹ , Nassima Bouzidi ¹ , Ana Topf ³ , Emmanuelle Lacène ⁶ , Ganaelle Remerand ⁷ , Anne-Marie Beaufrere ⁸ , Céline Pebrel-Richard ⁹ , Julien Thevenon ¹⁰ , Salima El Chehadeh-Djebbar ¹¹ , Laurence Faivre ¹⁰ , Yannis Duffourd ¹² , Federica Ricci ¹³ , Tiziana Mongini ¹³ , Chiara Fiorillo ¹⁴ , Guja Astrea ¹⁵ , Carmen Magdalena Burloiu ¹⁶ , Niculina Butoianu ¹⁶ , Carmen Sandu ¹⁶ , Laurent Servais ¹⁷ , Gisèle Bonne ¹⁷ , Isabelle Nelson ¹⁷ , Isabelle Desguerre ¹⁸ , Marie-Christine Nougues ¹⁹ , Benoit Bœuf ²⁰ , Norma Romero ²¹ , Jocelyn Laporte ²² , Anne Boland ²³ , Doris Lechner ²³ , Jean-François Deleuze ²³ , Bertrand Fontaine ⁵ , Laure Strochlic ¹ , Hanns Lochmuller ³ , Bruno Eymard ²⁴ , Michèle Mayer ¹⁹ , Sophie Nicole ²⁵

Affiliations

1. Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Université Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, 75013 Paris, France.
2. Membrane transport group, Neurophotonics Laboratory, CNRS UMR8250, Sorbonne Paris Cité-Paris Descartes University, 75005 Paris, France.
3. The John Walton Muscular Dystrophy Research Centre, MRC Centre for Neuromuscular Diseases, Institute of Genetic Medicine, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK.
4. Service de Génétique Médicale, Centre de référence Auvergne-Limousin, Neuropathies Périphériques Rares et Maladies Neuromusculaires, Centre Hospitalier Universitaire de Clermont-Ferrand, 63000 Clermont-Ferrand, France.
5. Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Université Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, 75013 Paris, France; AP-HP, Hôpital Pitié-Salpêtrière, 75013 Paris, France.
6. AP-HP, Hôpital Pitié-Salpêtrière, 75013 Paris, France; Unité de pathologies neuromusculaires, Institut de Myologie, Sorbonne Universités, UPMC Université Paris 06 UMRS 974, Inserm U974, CNRS UMR 7215, 75013 Paris, France.
7. Service de Néonatologie, Centre Hospitalier Universitaire de Clermont-Ferrand, 63000 Clermont-Ferrand, France.
8. Service d'Anatomie et Cytologie pathologiques, Centre Hospitalier Universitaire de Clermont-Ferrand, 63000 Clermont-Ferrand, France.
9. Service de Cytogénétique Médicale, Centre Hospitalier Universitaire de Clermont-Ferrand, 63000 Clermont-Ferrand, France.
10. Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement (TRANSLAD), Centre Hospitalier Universitaire Dijon, 21079 Dijon, France; Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs de l'Inter-région Est, Centre Hospitalier Universitaire Dijon, 21079 Dijon, France.
11. Service de génétique médicale, Institut de génétique médicale d'Alsace (IGMA), Hôpitaux Universitaires de Strasbourg, Hôpital de Hautepierre, 67098 Strasbourg, France.
12. Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement (TRANSLAD), Centre Hospitalier Universitaire Dijon, 21079 Dijon, France.
13. Center for Neuromuscular Diseases, Child Neurology and Psychiatry Unit, Regina Margherita Children Hospital, and Department of Neurosciences, University of Torino, 10124 Torino, Italy.
14. Molecular Medicine, IRCCS Fondazione Stella Maris, Calambrone, 56018 Pisa, Italy.
15. Department of Developmental Neuroscience, IRCCS Stella Maris Foundation, Calambrone, 56018 Pisa, Italy.
16. Alexandru Obregia Clinical Hospital, sos Berceni 10-12, 041914 Bucharest, Romania.
17. Sorbonne Universités, UPMC Univ Paris 06, INSERM UMRS974, CNRS FRE3617, Center of Research in Myology, Myology Institute, 75013 Paris, France.
18. Centre de Référence des Maladies Neuromusculaires de l'Ouest Parisien, Hôpital Necker-Enfants Malades, 75743 Paris, France.
19. Neuropédiatrie et Unité d'électrophysiologie clinique, Centre de Référence des Maladies Neuromusculaires de l'EST parisien et DHU I2B, Hôpital d'Enfants Armand Trousseau, 75012 Paris, France.
20. Service de réanimation néonatale et pédiatrique Hôpital Estaing CHU de Clermont Ferrand, 63000 Clermont-Ferrand, France.
21. Unité de pathologies neuromusculaires, Institut de Myologie, Sorbonne Universités, UPMC Université Paris 06 UMRS 974, Inserm U974, CNRS UMR 7215, 75013 Paris, France.
22. Departement Médecine Translationnelle et Neurogénétique, Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS UMR 7104, Inserm U 964, 67404 Illkirch, France; Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, 67000 Strasbourg, France.
23. Centre National de Génotypage (CNG), 91057 Evry, France.
24. Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Université Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, 75013 Paris, France; AP-HP, Hôpital Pitié-Salpêtrière, 75013 Paris, France; Sorbonne Universités, UPMC Univ Paris 06, INSERM UMRS974, CNRS FRE3617, Center of Research in Myology, Myology Institute, 75013 Paris, France.
25. Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Université Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, 75013 Paris, France. Electronic address: [email protected].

Abstract

The neuromuscular junction (NMJ) is one of the best-studied cholinergic synapses. Inherited defects of peripheral neurotransmission result in congenital myasthenic syndromes (CMSs), 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.