Role of Serine 263 in the Human Choline Transporter 1 and Congenital Myasthenic Syndrome
Bibliographic record
Abstract
Disruptions of the neuromuscular junction (NMJ) result in congenital myasthenic syndromes (CMS). CMS is characterized by a range of phenotypes including muscle weakness, apnoeas, akinesia or even death. CMS type 20 is caused by mutations in the SLC5A7 gene which encodes for the choline transporter (CHT1). CHT1 re‐uptake of choline is a requirement for acetylcholine synthesis and NMJ function. The 13 transmembrane domain CHT1 protein is also thought to be phosphorylated at several sites but the role of phosphorylation remains unknown. We have recently reported the missense recessive variant c.C788>T in SLC5A7 (NM_021815.4), in a family with a history of CMS using whole exome sequencing. This variant encodes a p.S263F substitution in CHT1 and results in a complete loss of transport function despite a normal plasma membrane localization. To assess whether a change in phosphorylation and/or charge/size of position 263 results in altered transport function, three substitutions were introduced into CHT1: p.S263A, and phosphomimetics p.S263D and p.S263E. Upon expression in HEK293 cells and the utilization of cell surface biotinylation experiments, we found that WT, p.S263F and p.S263A mutants were present at the plasma membrane. Radioactive transport assays indicated that the p.S263A mutant retained a high level of transport activity while the p.S263D and p.S263E mutants were non‐functional. Immobilized metal affinity electrophoresis suggests that wild‐type CHT1 may be more phosphorylated than the p.S263F CHT1 mutant. These results support the essential role of the Serine 263 residue in CHT1 choline transport possibly via altering its phosphorylation status as well as size/charge at this position.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".