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

2.50
Hdl Handle:
http://hdl.handle.net/11287/620516
Title:
Choline transporter mutations in severe congenital myasthenic syndrome disrupt transporter localization.
Authors:
Wang, H.; Salter, C. G.; Refai, O.; Hardy, H.; Barwick, K. E. S.; Akpulat, U.; Kvarnung, M.; Chioza, B. A.; Harlalka, G.; Taylan, F.; Sejersen, T.; Wright, J.; Zimmerman, H. H.; Karakaya, M.; Stüve, B.; Weis, J.; Schara, U.; Russell, M. A.; Abdul-Rahman, O. A.; Chilton, J.; Blakely, R. D.; Baple, E. L.; Cirak, S.; Crosby, Andrew H.
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 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.
Citation:
Choline transporter mutations in severe congenital myasthenic syndrome disrupt transporter localization. 2017, 140 (11):2838-2850 Brain
Publisher:
Oxford Journals
Journal:
Brain : a journal of neurology
Issue Date:
1-Nov-2017
URI:
http://hdl.handle.net/11287/620516
DOI:
10.1093/brain/awx249
PubMed ID:
29088354
Additional Links:
https://academic.oup.com/brain/article-lookup/doi/10.1093/brain/awx249
Type:
Journal Article
Language:
en
ISSN:
1460-2156
Appears in Collections:
Honorary contracts publications; 2017 RD&E publications

Full metadata record

DC FieldValue Language
dc.contributor.authorWang, H.en
dc.contributor.authorSalter, C. G.en
dc.contributor.authorRefai, O.en
dc.contributor.authorHardy, H.en
dc.contributor.authorBarwick, K. E. S.en
dc.contributor.authorAkpulat, U.en
dc.contributor.authorKvarnung, M.en
dc.contributor.authorChioza, B. A.en
dc.contributor.authorHarlalka, G.en
dc.contributor.authorTaylan, F.en
dc.contributor.authorSejersen, T.en
dc.contributor.authorWright, J.en
dc.contributor.authorZimmerman, H. H.en
dc.contributor.authorKarakaya, M.en
dc.contributor.authorStüve, B.en
dc.contributor.authorWeis, J.en
dc.contributor.authorSchara, U.en
dc.contributor.authorRussell, M. A.en
dc.contributor.authorAbdul-Rahman, O. A.en
dc.contributor.authorChilton, J.en
dc.contributor.authorBlakely, R. D.en
dc.contributor.authorBaple, E. L.en
dc.contributor.authorCirak, S.en
dc.contributor.authorCrosby, Andrew H.en
dc.date.accessioned2017-11-21T10:07:33Z-
dc.date.available2017-11-21T10:07:33Z-
dc.date.issued2017-11-01-
dc.identifier.citationCholine transporter mutations in severe congenital myasthenic syndrome disrupt transporter localization. 2017, 140 (11):2838-2850 Brainen
dc.identifier.issn1460-2156-
dc.identifier.pmid29088354-
dc.identifier.doi10.1093/brain/awx249-
dc.identifier.urihttp://hdl.handle.net/11287/620516-
dc.description.abstractThe 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.en
dc.language.isoenen
dc.publisherOxford Journalsen
dc.relation.urlhttps://academic.oup.com/brain/article-lookup/doi/10.1093/brain/awx249en
dc.rightsArchived with thanks to Brain : a journal of neurologyen
dc.subjectWessex Classification Subject Headings::Neurologyen
dc.subject.meshAnimals-
dc.subject.meshAnimals, Genetically Modified-
dc.subject.meshAtrophy-
dc.subject.meshAxons-
dc.subject.meshBrain-
dc.subject.meshCaenorhabditis elegans-
dc.subject.meshCaenorhabditis elegans Proteins-
dc.subject.meshChild, Preschool-
dc.subject.meshFemale-
dc.subject.meshHEK293 Cells-
dc.subject.meshHomozygote-
dc.subject.meshHumans-
dc.subject.meshInfant-
dc.subject.meshMale-
dc.subject.meshMembrane Transport Proteins-
dc.subject.meshMutation, Missense-
dc.subject.meshMyasthenic Syndromes, Congenital-
dc.subject.meshNeurodevelopmental Disorders-
dc.subject.meshPedigree-
dc.subject.meshPresynaptic Terminals-
dc.subject.meshProtein Transport-
dc.subject.meshSymporters-
dc.titleCholine transporter mutations in severe congenital myasthenic syndrome disrupt transporter localization.en
dc.typeJournal Articleen
dc.identifier.journalBrain : a journal of neurologyen
dc.type.versionPublisheden

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