Wang, Haicui, Salter, Claire G., Refai, Osama ORCID: 0000-0002-5870-5236, Hardy, Holly, Barwick, Katy E. S., Akpulat, Ugur, Kvarnung, Malin, Chioza, Barry A., Harlalka, Gaurav, Taylan, Fulya ORCID: 0000-0002-2907-0235, Sejersen, Thomas, Wright, Jane, Zimmerman, Holly H., Karakaya, Mert, Stueve, Burkhardt, Weis, Joachim, Schara, Ulrike, Russell, Mark A., Abdul-Rahman, Omar A., Chilton, John, Blakely, Randy D., Baple, Emma L., Cirak, Sebahattin and Crosby, Andrew H. (2017). Choline transporter mutations in severe congenital myasthenic syndrome disrupt transporter localization. Brain, 140. S. 2838 - 2851. OXFORD: OXFORD UNIV PRESS. ISSN 1460-2156

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Wang, HaicuiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Salter, Claire G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Refai, OsamaUNSPECIFIEDorcid.org/0000-0002-5870-5236UNSPECIFIED
Hardy, HollyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Barwick, Katy E. S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Akpulat, UgurUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kvarnung, MalinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chioza, Barry A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Harlalka, GauravUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Taylan, FulyaUNSPECIFIEDorcid.org/0000-0002-2907-0235UNSPECIFIED
Sejersen, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wright, JaneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zimmerman, Holly H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Karakaya, MertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stueve, BurkhardtUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weis, JoachimUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schara, UlrikeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Russell, Mark A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Abdul-Rahman, Omar A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chilton, JohnUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Blakely, Randy D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baple, Emma L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cirak, SebahattinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Crosby, Andrew H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-212524
DOI: 10.1093/brain/awx249
Journal or Publication Title: Brain
Volume: 140
Page Range: S. 2838 - 2851
Date: 2017
Publisher: OXFORD UNIV PRESS
Place of Publication: OXFORD
ISSN: 1460-2156
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
VII DHMN-VII; TRANSMISSION; ENDOCYTOSIS; EXPRESSION; UNDERLIES; ELEGANS; GENEMultiple languages
Clinical Neurology; NeurosciencesMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/21252

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