Discovery of choline transporter mutations in a novel form of congenital myasthenic syndrom facilitates treatment


of patients reported by the teams of Sebahattin Cirak (Dept. of Pediatrics, Univ. Hospital of Cologne and the CMMC), Andrew Crosby and Emma Baple (University Exeter, UK).

Congenital myasthenic syndrome (CMS) is a group of conditions characterized by fatigable muscle weakness (myasthenia) of skeletal muscle affecting ocular, bulbar, limb muscles that worsens with physical exertion with onset at or shortly after birth or in early childhood.

The severity of the myasthenia varies greatly. Affected infants and children who become tired very easily may show a wide spectrum of physically disabilities ranging from swallowing problems, respiratory problems requiring mechanical ventilation and the inability to crawl, sit or walk.

The CMS comprises comprises heterogeneous genetic diseases that are characterized by compromised neuromuscular transmission resulting in an altered transduction of signals from the nerve endings to the skeletal muscle. This impaired signal transduction leads to reduced variable muscle contraction frequency and strength. The presynaptic, high-affinity choline transporter (CHT, SLC5A7) is a critical determinant of signalling by the neurotransmitter acetylcholine at both central and peripheral cholinergic synapses, including the neuromuscular junction.

In a collaborative setting research teams of Sebahattin Cirak (Department of Pediatrics, Univ. Hospital of Cologne and the CMMC), Andrew Crosby and Emma Baple (University Exeter, UK) have identified novel mutations in the SLC5A7 gene as cause of a novel congenital myasthenic syndrome.

Dr. Sebahattin Cirak comments: “Together with our cooperating partners we identified new genetic mutations in a gene called `SLC5A7’ that has been previously discovered by whole exome sequencing of affected infants. The SLC5A7 gene coding for a choline transporter protein that is important for the recycling of choline, a chemical molecule which acts as acetylcholine as signaling molecule at the nerve endings (neuromuscular endplate). Various cell models studied in the laboratory with the SLC5A7 gene defect showed an almost complete loss of their signaling ability.”

Experiments with 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 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. Based on the discovery of disease causing mutations patients could be treated with precise drugs to improve the signal transduction and amelioration of clinical symptoms in patients. This work is an example of translational and collaborative international research excellence for genetically driven precision medicine.

The results have been published in Brain on November 01, 2017.
Choline transporter mutations in severe congenital myasthenic syndrome disrupt transporter localization.
Wang H*, Salter CG*, Refai O*, Hardy H, Barwick KES, Akpulat U, Kvarnung M, Chioza BA, Harlalka G, Taylan F, Sejersen T, Wright J, Zimmerman HH, Karakaya M, Stüve B, Weis J, Schara U, Russell MA, Abdul-Rahman OA, Chilton J, Blakely RD, Baple EL and Cirak S*, Crosby AH*.
Brain. 2017 Nov 1;140(11):2838-2850. doi: 10.1093/brain/awx249. PubMed PMID: 29088354.

*equally contributing first authors, # equally corresponding senior authors

For further information, please contact:          
Dr. Sebahattin Cirak  
Center of Pediatrics and Adolescent Medicine and
Center for Molecular Medicine Cologne