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Brain. 2017 Nov 1;140(11):2838-2850. doi: 10.1093/brain/awx249.

Choline transporter mutations in severe congenital myasthenic syndrome disrupt transporter localization.

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University Hospital Cologne, Department of Pediatrics, Kerpener Str. 62, 50937 Cologne, Germany.
Center for Molecular Medicine Cologne (CMMC), University of Cologne, Robert-Koch-Str. 21, 50931 Cologne, Germany.
RILD Wellcome Wolfson Centre, Royal Devon and Exeter NHS Foundation Trust, Barrack Road, Exeter, EX2 5DW, UK.
Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton, SO16 6YD, UK.
Department of Biomedical Science, Charles E. Schmidt College of Medicine and Brain Institute, Florida Atlantic University, Jupiter, FL, USA.
Kastamonu University, 37150 Kastamonu, Turkey.
Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, 17176 Stockholm, Sweden.
Department of Clinical Genetics, Karolinska University Hospital, 17176 Stockholm, Sweden.
Science for Life Laboratory, Karolinska Institutet Science Park, 17121 Stockholm, Sweden.
Department of Women's and Children's Health, Division of Pediatric Neurology, Karolinska Institutet, 17176 Stockholm, Sweden.
Department of Pharmacology, Vanderbilt University, Nashville, TN, USA.
Division of Medical Genetics, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA.
Children's Hospital Social Pediatric Center, 50735 Cologne, Germany.
Institute of Neuropathology and Jülich Aachen Research Alliance (JARA) Brain Translational Medicine, RWTH Aachen University, 52074 Aachen, Germany.
University Children's Hospital Essen, Essen, Germany.
Department of Pediatrics, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA.


The presynaptic, high-affinity choline transporter is a critical determinant of signalling by the neurotransmitter acetylcholine at both central and peripheral cholinergic synapses, including the neuromuscular junction. Here we describe an autosomal recessive presynaptic congenital myasthenic syndrome presenting with a broad clinical phenotype due to homozygous choline transporter missense mutations. The clinical phenotype ranges from the classical presentation of a congenital myasthenic syndrome in one patient (p.Pro210Leu), to severe neurodevelopmental delay with brain atrophy (p.Ser94Arg) and extend the clinical outcomes to a more severe spectrum with infantile lethality (p.Val112Glu). Cells transfected with mutant transporter construct revealed a virtually complete loss of transport activity that was paralleled by a reduction in transporter cell surface expression. Consistent with these findings, studies to determine the impact of gene mutations on the trafficking of the Caenorhabditis elegans choline transporter orthologue revealed deficits in transporter export to axons and nerve terminals. These findings contrast with our previous findings in autosomal dominant distal hereditary motor neuropathy of a dominant-negative frameshift mutation at the C-terminus of choline transporter that was associated with significantly reduced, but not completely abrogated choline transporter function. Together our findings define divergent neuropathological outcomes arising from different classes of choline transporter mutation with distinct disease processes and modes of inheritance. These findings underscore the essential role played by the choline transporter in sustaining acetylcholine neurotransmission at both central and neuromuscular synapses, with important implications for treatment and drug selection.


CHT; CHT trafficking; SLC5A7; choline uptake; congenital myasthenic syndrome

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