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Choline transporter mutations in severe congenital myasthenic syndrome disrupt transporter localization      
Yazarlar
Haicui Wang
Claire G. Salter
Osama Refai
Holly Hardy
Katy E. S. Barwick
Dr. Öğr. Üyesi Uğur AKPULAT
Kastamonu Üniversitesi, Türkiye
Malin Kvarnung
Barry A. Chioza
Gaurav Harlalka
Fulya Taylan
Thomas Sejersen
Jane Wright
Holly H. Zimmerman
Mert Karakaya
Burkhardt Stueve
Joachim Weis
Ulrike Schara
Mark A. Russell
Omar A. Abdul-Rahman
John Chilton
Randy D. Blakely
Emma L. Baple
Sebahattin Cirak
Andrew H. Crosby
Özet
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.
Anahtar Kelimeler
choline uptake | CHT | CHT trafficking | congenital myasthenic syndrome | SLC5A7
Makale Türü Özgün Makale
Makale Alt Türü SSCI, AHCI, SCI, SCI-Exp dergilerinde yayımlanan tam makale
Dergi Adı BRAIN
Dergi ISSN 0006-8950
Dergi Tarandığı Indeksler SCI
Makale Dili İngilizce
Basım Tarihi 01-2017
Cilt No 140
Sayı 11
Sayfalar 2838 / 2850
Doi Numarası 10.1093/brain/awx249