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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.

SUBMITTER: Bauche S 

PROVIDER: S-EPMC5011057 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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

Bauché Stéphanie S   O'Regan Seana S   Azuma Yoshiteru Y   Laffargue Fanny F   McMacken Grace G   Sternberg Damien D   Brochier Guy G   Buon Céline C   Bouzidi Nassima N   Topf Ana A   Lacène Emmanuelle E   Remerand Ganaelle G   Beaufrere Anne-Marie AM   Pebrel-Richard Céline C   Thevenon Julien J   El Chehadeh-Djebbar Salima S   Faivre Laurence L   Duffourd Yannis Y   Ricci Federica F   Ricci Federica F   Mongini Tiziana T   Fiorillo Chiara C   Astrea Guja G   Burloiu Carmen Magdalena CM   Butoianu Niculina N   Sandu Carmen C   Servais Laurent L   Bonne Gisèle G   Nelson Isabelle I   Desguerre Isabelle I   Nougues Marie-Christine MC   Bœuf Benoit B   Romero Norma N   Laporte Jocelyn J   Boland Anne A   Lechner Doris D   Deleuze Jean-François JF   Fontaine Bertrand B   Strochlic Laure L   Lochmuller Hanns H   Eymard Bruno B   Mayer Michèle M   Nicole Sophie S  

American journal of human genetics 20160825 3


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 hi  ...[more]

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