Muscle acetylcholine receptor conversion into chloride conductance at positive potentials by a single mutation.

Charge selectivity forms the basis of cellular excitation or inhibition by Cys-loop ligand-gated ion channels (LGICs), and is essential for physiological receptor function. There are no reports of naturally occurring mutations in LGICs associated with the conversion of charge selectivity. Here, we report on a CHRNA1 mutation (α1Leu251Arg) in a patient with congenital myasthenic syndrome associated with transformation of the muscle acetylcholine receptor (AChR) into an inhibitory channel. Performing patch-clamp experiments, the AChR was found to be converted into chloride conductance at positive potentials, whereas whole-cell currents at negative potentials, although markedly reduced, were still carried by sodium. Umbrella sampling molecular dynamics simulations revealed constriction of the channel pore radius to 2.4 Å as a result of the mutation, which required partial desolvation of the ions in order to permeate the pore. Ion desolvation was associated with an energetic penalty that was compensated for by the favorable electrostatic interaction of the positively charged arginines with chloride. These findings reveal a mechanism for the transformation of the muscle AChR into an inhibitory channel in a clinical context.

Retinal vein occlusions and mortality: the Beijing Eye Study.

PURPOSE: To assess the association between retinal vein occlusion (RVO) and mortality in a population-based setting. DESIGN: Population-based, longitudinal study. METHODS: At baseline in 2001, the Beijing Eye Study examined 4,335 subjects for RVO with a frequency of detected vein occlusions of 61 (1.4%) in 4,335 subjects. In 2006, all study participants were invited for a follow-up examination. RESULTS: Of the 4,335 subjects, 3,195 (73.7%) returned for follow-up examination, whereas 132 (3.0%) subjects had died and 1,008 (23.3%) subjects declined to be re-examined or had moved away. For the subjects younger than 70 years or than 65 years, respectively, RVO was associated significantly with an increased mortality rate (P = .05; 95% confidence interval [CI], 0.995 to 8.26; and P = .001; 95% CI, 2.11 to 18.73, respectively). CONCLUSIONS: RVO in relatively young persons may signal a significant risk of mortality.