Universität zu Köln

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:	Creators Email ORCID ORCID Put Code Wang, Haicui UNSPECIFIED UNSPECIFIED UNSPECIFIED Salter, Claire G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Refai, Osama UNSPECIFIED orcid.org/0000-0002-5870-5236 UNSPECIFIED Hardy, Holly UNSPECIFIED UNSPECIFIED UNSPECIFIED Barwick, Katy E. S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Akpulat, Ugur UNSPECIFIED UNSPECIFIED UNSPECIFIED Kvarnung, Malin UNSPECIFIED UNSPECIFIED UNSPECIFIED Chioza, Barry A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Harlalka, Gaurav UNSPECIFIED UNSPECIFIED UNSPECIFIED Taylan, Fulya UNSPECIFIED orcid.org/0000-0002-2907-0235 UNSPECIFIED Sejersen, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Wright, Jane UNSPECIFIED UNSPECIFIED UNSPECIFIED Zimmerman, Holly H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Karakaya, Mert UNSPECIFIED UNSPECIFIED UNSPECIFIED Stueve, Burkhardt UNSPECIFIED UNSPECIFIED UNSPECIFIED Weis, Joachim UNSPECIFIED UNSPECIFIED UNSPECIFIED Schara, Ulrike UNSPECIFIED UNSPECIFIED UNSPECIFIED Russell, Mark A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Abdul-Rahman, Omar A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Chilton, John UNSPECIFIED UNSPECIFIED UNSPECIFIED Blakely, Randy D. UNSPECIFIED UNSPECIFIED UNSPECIFIED Baple, Emma L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Cirak, Sebahattin UNSPECIFIED UNSPECIFIED UNSPECIFIED Crosby, Andrew H. UNSPECIFIED UNSPECIFIED UNSPECIFIED
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:	Keywords Language VII DHMN-VII; TRANSMISSION; ENDOCYTOSIS; EXPRESSION; UNDERLIES; ELEGANS; GENE Multiple languages Clinical Neurology; Neurosciences Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/21252