title: Defective presynaptic choline transport underlies hereditary motor neuropathy.
abstract: The neuromuscular junction (NMJ) is a specialized synapse with a complex molecular architecture that provides for reliable transmission between the nerve terminal and muscle fiber. Using linkage analysis and whole-exome sequencing of DNA samples from subjects with distal hereditary motor neuropathy type VII, we identified a mutation in SLC5A7, which encodes the presynaptic choline transporter (CHT), a critical determinant of synaptic acetylcholine synthesis and release at the NMJ. This dominantly segregating SLC5A7 mutation truncates the encoded product just beyond the final transmembrane domain, eliminating cytosolic-C-terminus sequences known to regulate surface transporter trafficking. Choline-transport assays in both transfected cells and monocytes from affected individuals revealed significant reductions in hemicholinium-3-sensitive choline uptake, a finding consistent with a dominant-negative mode of action. The discovery of CHT dysfunction underlying motor neuropathy identifies a biological basis for this group of conditions and widens the spectrum of disorders that derive from impaired NMJ transmission. Our findings compel consideration of mutations in SLC5A7 or its functional partners in relation to unexplained motor neuronopathies.
authors.affiliation: Centre for Human Genetics, St. George's University of London, Cranmer Terrace, London SW17 0RE, UK.
authors.forename: Katy E S
authors.initials: KE
authors.lastname: Barwick
authors.forename: Jane
authors.initials: J
authors.lastname: Wright
authors.forename: Saeed
authors.initials: S
authors.lastname: Al-Turki
authors.forename: Meriel M
authors.initials: MM
authors.lastname: McEntagart
authors.forename: Ajith
authors.initials: A
authors.lastname: Nair
authors.forename: Barry
authors.initials: B
authors.lastname: Chioza
authors.forename: Ali
authors.initials: A
authors.lastname: Al-Memar
authors.forename: Hamid
authors.initials: H
authors.lastname: Modarres
authors.forename: Mary M
authors.initials: MM
authors.lastname: Reilly
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Dick
authors.forename: Alicia M
authors.initials: AM
authors.lastname: Ruggiero
authors.forename: Randy D
authors.initials: RD
authors.lastname: Blakely
authors.forename: Matt E
authors.initials: ME
authors.lastname: Hurles
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Crosby
mesh_terms: D000328:Adult; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D016472:Motor Neuron Disease / Q000235:genetics* / Q000378:metabolism*; D010375:Pedigree; D010641:Phenotype; D017729:Presynaptic Terminals / Q000378:metabolism*; D027981:Symporters / Q000235:genetics* / Q000378:metabolism
chemical_list: C510731:SLC5A7 protein, human; D027981:Symporters