title: Impaired Presynaptic High-Affinity Choline Transporter Causes a Congenital Myasthenic Syndrome with Episodic Apnea.
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.
authors: 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.
authors: Stéphanie
authors: S
authors: Bauché
authors: Membrane transport group, Neurophotonics Laboratory, CNRS UMR8250, Sorbonne Paris Cité-Paris Descartes University, 75005 Paris, France.
authors: Seana
authors: S
authors: O'Regan
authors: 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.
authors: Yoshiteru
authors: Y
authors: Azuma
authors: 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.
authors: Fanny
authors: F
authors: Laffargue
authors: 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.
authors: Grace
authors: G
authors: McMacken
authors: 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.
authors: Damien
authors: D
authors: Sternberg
authors: 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.
authors: Guy
authors: G
authors: Brochier
authors: 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.
authors: Céline
authors: C
authors: Buon
authors: 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.
authors: Nassima
authors: N
authors: Bouzidi
authors: 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.
authors: Ana
authors: A
authors: Topf
authors: 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.
authors: Emmanuelle
authors: E
authors: Lacène
authors: Service de Néonatologie, Centre Hospitalier Universitaire de Clermont-Ferrand, 63000 Clermont-Ferrand, France.
authors: Ganaelle
authors: G
authors: Remerand
authors: Service d'Anatomie et Cytologie pathologiques, Centre Hospitalier Universitaire de Clermont-Ferrand, 63000 Clermont-Ferrand, France.
authors: Anne-Marie
authors: AM
authors: Beaufrere
authors: Service de Cytogénétique Médicale, Centre Hospitalier Universitaire de Clermont-Ferrand, 63000 Clermont-Ferrand, France.
authors: Céline
authors: C
authors: Pebrel-Richard
authors: 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.
authors: Julien
authors: J
authors: Thevenon
authors: Service de génétique médicale, Institut de génétique médicale d'Alsace (IGMA), Hôpitaux Universitaires de Strasbourg, Hôpital de Hautepierre, 67098 Strasbourg, France.
authors: Salima
authors: S
authors: El Chehadeh-Djebbar
authors: 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.
authors: Laurence
authors: L
authors: Faivre
authors: Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement (TRANSLAD), Centre Hospitalier Universitaire Dijon, 21079 Dijon, France.
authors: Yannis
authors: Y
authors: Duffourd
authors: Center for Neuromuscular Diseases, Child Neurology and Psychiatry Unit, Regina Margherita Children Hospital, and Department of Neurosciences, University of Torino, 10124 Torino, Italy.
authors: Federica
authors: F
authors: Ricci
authors: Center for Neuromuscular Diseases, Child Neurology and Psychiatry Unit, Regina Margherita Children Hospital, and Department of Neurosciences, University of Torino, 10124 Torino, Italy.
authors: Tiziana
authors: T
authors: Mongini
authors: Molecular Medicine, IRCCS Fondazione Stella Maris, Calambrone, 56018 Pisa, Italy.
authors: Chiara
authors: C
authors: Fiorillo
authors: Department of Developmental Neuroscience, IRCCS Stella Maris Foundation, Calambrone, 56018 Pisa, Italy.
authors: Guja
authors: G
authors: Astrea
authors: Alexandru Obregia Clinical Hospital, sos Berceni 10-12, 041914 Bucharest, Romania.
authors: Carmen Magdalena
authors: CM
authors: Burloiu
authors: Alexandru Obregia Clinical Hospital, sos Berceni 10-12, 041914 Bucharest, Romania.
authors: Niculina
authors: N
authors: Butoianu
authors: Alexandru Obregia Clinical Hospital, sos Berceni 10-12, 041914 Bucharest, Romania.
authors: Carmen
authors: C
authors: Sandu
authors: Sorbonne Universités, UPMC Univ Paris 06, INSERM UMRS974, CNRS FRE3617, Center of Research in Myology, Myology Institute, 75013 Paris, France.
authors: Laurent
authors: L
authors: Servais
authors: Sorbonne Universités, UPMC Univ Paris 06, INSERM UMRS974, CNRS FRE3617, Center of Research in Myology, Myology Institute, 75013 Paris, France.
authors: Gisèle
authors: G
authors: Bonne
authors: Sorbonne Universités, UPMC Univ Paris 06, INSERM UMRS974, CNRS FRE3617, Center of Research in Myology, Myology Institute, 75013 Paris, France.
authors: Isabelle
authors: I
authors: Nelson
authors: Centre de Référence des Maladies Neuromusculaires de l'Ouest Parisien, Hôpital Necker-Enfants Malades, 75743 Paris, France.
authors: Isabelle
authors: I
authors: Desguerre
authors: 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.
authors: Marie-Christine
authors: MC
authors: Nougues
authors: Service de réanimation néonatale et pédiatrique Hôpital Estaing CHU de Clermont Ferrand, 63000 Clermont-Ferrand, France.
authors: Benoit
authors: B
authors: Bœuf
authors: Unité de pathologies neuromusculaires, Institut de Myologie, Sorbonne Universités, UPMC Université Paris 06 UMRS 974, Inserm U974, CNRS UMR 7215, 75013 Paris, France.
authors: Norma
authors: N
authors: Romero
authors: 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.
authors: Jocelyn
authors: J
authors: Laporte
authors: Centre National de Génotypage (CNG), 91057 Evry, France.
authors: Anne
authors: A
authors: Boland
authors: Centre National de Génotypage (CNG), 91057 Evry, France.
authors: Doris
authors: D
authors: Lechner
authors: Centre National de Génotypage (CNG), 91057 Evry, France.
authors: Jean-François
authors: JF
authors: Deleuze
authors: 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.
authors: Bertrand
authors: B
authors: Fontaine
authors: 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.
authors: Laure
authors: L
authors: Strochlic
authors: 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.
authors: Hanns
authors: H
authors: Lochmuller
authors: 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.
authors: Bruno
authors: B
authors: Eymard
authors: 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.
authors: Michèle
authors: M
authors: Mayer
authors: 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: sophie.nicole@inserm.fr.
authors: Sophie
authors: S
authors: Nicole
mesh_terms: D000293:Adolescent; D001049:Apnea / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D001176:Arthrogryposis / Q000150:complications / Q000235:genetics; D002091:Butyrylcholinesterase / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D059329:Cholinergic Neurons / Q000378:metabolism / Q000473:pathology; D004252:DNA Mutational Analysis; D059472:Exome / Q000235:genetics; D005260:Female; D005808:Genes, Recessive / Q000235:genetics; D057809:HEK293 Cells; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009123:Muscle Hypotonia / Q000235:genetics; D018908:Muscle Weakness / Q000150:complications / Q000235:genetics / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D009157:Myasthenia Gravis / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009469:Neuromuscular Junction / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D017729:Presynaptic Terminals / Q000378:metabolism* / Q000473:pathology; D027981:Symporters / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D009435:Synaptic Transmission
chemical_list: C510731:SLC5A7 protein, human; D027981:Symporters; D002091:Butyrylcholinesterase