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

Brain : a Journal of Neurology
Haicui WangAndrew H Crosby

Abstract

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 fr...Continue Reading

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Citations

Mar 28, 2018·Neurology. Genetics·Claire G SalterAndrew H Crosby
Jun 6, 2019·Journal of Human Genetics·Hormos Salimi DafsariSebahattin Cirak
Feb 28, 2019·Orphanet Journal of Rare Diseases·Josef Finsterer
Dec 20, 2019·Brain : a Journal of Neurology·Christina R FagerbergMarica Bakovic
Oct 14, 2020·American Journal of Medical Genetics. Part a·Daniel BamborschkeSebahattin Cirak
Nov 20, 2020·Brain : a Journal of Neurology·Danique Beijer, Jonathan Baets
Mar 1, 2021·European Journal of Pharmacology·Takashi OkudaHidemi Misawa
Aug 10, 2020·Neurochemistry International·O A Ojiakor, R J Rylett

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