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

Stephanie Bauche; Seana O'Regan; Yoshiteru Azuma; Fanny Laffargue; Grace McMacken; Damien Sternberg; Guy Brochier; Celine Buon; Nassima Bouzidi; Ana Topf; Emmanuelle Lacene; Ganaelle Remerand; Anne-Marie Beaufrere; Celine Pebrel-Richard; Julien Thevenon; Salima El Chehadeh-Djebbar; Laurence Faivre; Yannis Duffourd; Federica Ricci; Tiziana Mongini; Chiara Fiorillo; Guja Astrea; Carmen Magdalena Burloiu; Niculina Butoianu; Carmen Sandu; Laurent Servais; Gisele Bonne; Isabelle Nelson; Isabelle Desguerre; Marie-Christine Nougues; Benoit Boeuf; Norma Romero; Jocelyn Laporte; Anne Boland; Doris Lechner; Jean-Francois Deleuze; Bertrand Fontaine; Laure Strochlic; Hanns Lochmuller; Bruno Eymard; Michele Mayer; Sophie Nicole

doi:10.1016/j.ajhg.2016.06.033

Retour

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

Article de revue

Avec comité de lecture

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

Stephanie Bauche, Seana O'Regan, Yoshiteru Azuma, Fanny Laffargue, Grace McMacken, Damien Sternberg, Guy Brochier, Celine Buon, Nassima Bouzidi, Ana Topf, …

American journal of human genetics, Vol.99(3), pp.753-761

01/09/2016

DOI: https://doi.org/10.1016/j.ajhg.2016.06.033

PMID: 27569547

Résumé

Genetics & Heredity

Life Sciences & Biomedicine

Science & Technology

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.

Indicateurs

1 Consultations de la notice

See more details

Détails

Titre: Impaired Presynaptic High-Affinity Choline Transporter Causes a Congenital Myasthenic Syndrome with Episodic Apnea
Créateurs - sans rôle: Stephanie Bauche - Univ Paris 06, Sorbonne Univ, Inst Cerveau & Moelle Epiniere, ICM,INSERM,U1127,CNRS,UMR 7225,UMR S 1127, F-75013 Paris, France
Seana O'Regan - Paris Descartes Univ, Membrane Transport Grp, Sorbonne Paris Cite, Neurophoton Lab,CNRS,UMR8250, F-75005 Paris, France
Yoshiteru Azuma - Newcastle Univ, John Walton Muscular Dystrophy Res Ctr, MRC Ctr Neuromuscular Dis, Inst Med Genet, Cent Pkwy, Newcastle Upon Tyne NE1 3BZ, Tyne & Wear, England
Fanny Laffargue - Ctr Hosp Univ Clermont Ferrand, Gen Med Serv, Ctr Reference Auvergne Limousin Neuropathies Peri, F-63000 Clermont Ferrand, France
Grace McMacken - Newcastle Univ, John Walton Muscular Dystrophy Res Ctr, MRC Ctr Neuromuscular Dis, Inst Med Genet, Cent Pkwy, Newcastle Upon Tyne NE1 3BZ, Tyne & Wear, England
Damien Sternberg - Univ Paris 06, Sorbonne Univ, Inst Cerveau & Moelle Epiniere, ICM,INSERM,U1127,CNRS,UMR 7225,UMR S 1127, F-75013 Paris, France
Guy Brochier - Assistance Publique – Hôpitaux de Paris
Celine Buon - Univ Paris 06, Sorbonne Univ, Inst Cerveau & Moelle Epiniere, ICM,INSERM,U1127,CNRS,UMR 7225,UMR S 1127, F-75013 Paris, France
Nassima Bouzidi - Univ Paris 06, Sorbonne Univ, Inst Cerveau & Moelle Epiniere, ICM,INSERM,U1127,CNRS,UMR 7225,UMR S 1127, F-75013 Paris, France
Ana Topf - Newcastle Univ, John Walton Muscular Dystrophy Res Ctr, MRC Ctr Neuromuscular Dis, Inst Med Genet, Cent Pkwy, Newcastle Upon Tyne NE1 3BZ, Tyne & Wear, England
Emmanuelle Lacene - Assistance Publique – Hôpitaux de Paris
Ganaelle Remerand - Ctr Hosp Univ Clermont Ferrand, Serv Neonatol, F-63000 Clermont Ferrand, France
Anne-Marie Beaufrere - Ctr Hosp Univ Clermont Ferrand, Serv Anat & Cytol Pathol, F-63000 Clermont Ferrand, France
Celine Pebrel-Richard - Ctr Hosp Univ Clermont Ferrand, Serv Cytogenet Med, F-63000 Clermont Ferrand, France
Julien Thevenon - Université de Bourgogne
Salima El Chehadeh-Djebbar - Hop Hautepierre, Inst Genet Med Alsace IGMA, Hop Univ Strasbourg, Serv Genet Med, F-67098 Strasbourg, France
Laurence Faivre - Université de Bourgogne
Yannis Duffourd - Université de Bourgogne
Federica Ricci - University of Turin
Tiziana Mongini - University of Turin
Chiara Fiorillo - IRCCS Fdn Stella Maris, Mol Med, I-56018 Pisa, Italy
Guja Astrea - IRCCS Stella Maris Fdn, Dept Dev Neurosci, I-56018 Pisa, Italy
Carmen Magdalena Burloiu - Alexandru Obregia Clin Hosp, Sos Berceni 10-12, Bucharest 041914, Romania
Niculina Butoianu - Alexandru Obregia Clin Hosp, Sos Berceni 10-12, Bucharest 041914, Romania
Carmen Sandu - Alexandru Obregia Clin Hosp, Sos Berceni 10-12, Bucharest 041914, Romania
Laurent Servais - Univ Paris 06, Sorbonne Univ, INSERM, Ctr Res Myol,Myol Inst,CNRS,FRE3617,UMRS974, F-75013 Paris, France
Gisele Bonne - Univ Paris 06, Sorbonne Univ, INSERM, Ctr Res Myol,Myol Inst,CNRS,FRE3617,UMRS974, F-75013 Paris, France
Isabelle Nelson - Univ Paris 06, Sorbonne Univ, INSERM, Ctr Res Myol,Myol Inst,CNRS,FRE3617,UMRS974, F-75013 Paris, France
Isabelle Desguerre - Hop Necker Enfants Malad, Ctr Reference Malad Neuromusculaires Ouest Parisi, F-75743 Paris, France
Marie-Christine Nougues - Hop Enfants Armand Trousseau, Neuropediat, F-75012 Paris, France
Benoit Boeuf - CHU Clermont Ferrand, Hop Estaing, Serv Reanimat Neonatale & Pediat, F-63000 Clermont Ferrand, France
Norma Romero - Univ Paris 06, Sorbonne Univ, Unite Pathol Neuromusculaires, Inst Myol,UMRS 974,INSERM,CNRS,UMR 7215,U974, F-75013 Paris, France
Jocelyn Laporte - Institut de génétique et de biologie moléculaire et cellulaire
Anne Boland - CNG, F-91057 Evry, France
Doris Lechner - CNG, F-91057 Evry, France
Jean-Francois Deleuze - CNG, F-91057 Evry, France
Bertrand Fontaine - Univ Paris 06, Sorbonne Univ, Inst Cerveau & Moelle Epiniere, ICM,INSERM,U1127,CNRS,UMR 7225,UMR S 1127, F-75013 Paris, France
Laure Strochlic - Univ Paris 06, Sorbonne Univ, Inst Cerveau & Moelle Epiniere, ICM,INSERM,U1127,CNRS,UMR 7225,UMR S 1127, F-75013 Paris, France
Hanns Lochmuller - Newcastle Univ, John Walton Muscular Dystrophy Res Ctr, MRC Ctr Neuromuscular Dis, Inst Med Genet, Cent Pkwy, Newcastle Upon Tyne NE1 3BZ, Tyne & Wear, England
Bruno Eymard - Univ Paris 06, Sorbonne Univ, Inst Cerveau & Moelle Epiniere, ICM,INSERM,U1127,CNRS,UMR 7225,UMR S 1127, F-75013 Paris, France
Michele Mayer - Hop Enfants Armand Trousseau, Neuropediat, F-75012 Paris, France
Sophie Nicole - Univ Paris 06, Sorbonne Univ, Inst Cerveau & Moelle Epiniere, ICM,INSERM,U1127,CNRS,UMR 7225,UMR S 1127, F-75013 Paris, France
Détails de publication: American journal of human genetics, Vol.99(3), pp.753-761
Éditeur: Elsevier
Nombre de pages: 9
Note de subvention: 305444; 305121 / European Union Seventh Framework Programme (FP7); Marie Curie Actions Fondation Maladies Rares within the Myocapture sequencing project ANR-10-IAIHU-06; ANR-10-INBS-09 / programs "Investissements d'avenir"; Agence Nationale de la Recherche (ANR) G1002274; 98482 / Medical Research Council UK; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) G1002274 / MRC; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) G1002274 / Medical Research Council; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) 20030 / AFM-Telethon; Association Francaise contre les Myopathies
Identifiants: 99139429109311
Unité académique: Institut de Génomique Fonctionnelle - IGF
Langue: English
Type de ressource: Journal article