Defective Presynaptic Choline Transport Underlies Hereditary Motor Neuropathy

• Published in: American journal of human genetics Vol. 91; no. 6; pp. 1103 - 1107
• Main Authors: Barwick, Katy E.S., Wright, Jane, Al-Turki, Saeed, McEntagart, Meriel M., Nair, Ajith, Chioza, Barry, Al-Memar, Ali, Modarres, Hamid, Reilly, Mary M., Dick, Katherine J., Ruggiero, Alicia M., Blakely, Randy D., Hurles, Matt E., Crosby, Andrew H.
• Format: Journal Article
• Language: English
• Published: Cambridge, MA Elsevier Inc 07.12.2012; Cell Press; Elsevier
• Subjects: Adult; Biological and medical sciences; Disease transmission; Female; Fundamental and applied biological sciences. Psychology; Genetic linkage; Genetics of eukaryotes. Biological and molecular evolution; Heredity; Humans; Male; Medical genetics; Medical sciences; Middle Aged; Molecular and cellular biology; Motor Neuron Disease - genetics; Motor Neuron Disease - metabolism; Mutation; Neuromuscular diseases; Pedigree; Phenotype; Presynaptic Terminals - metabolism; Symporters - genetics; Symporters - metabolism; Choleretic; Nervous system diseases; Choline; Genetics; Neuropathy; Hereditary; Transport; Genetic disease
• ISSN: 0002-9297; 1537-6605; 1537-6605
• DOI: 10.1016/j.ajhg.2012.09.019

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.