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Materials and Methods: Self-identified black South African POAG patients (215) and unaffected control participants (214) had ophthalmological examinations and DNA extraction. Potentially pathogenic MYOC variants were genotyped in the study population. Family members of participants with the mutations were screened for glaucoma clinically and for the mutations using Sanger sequencing.
Results: The following mutations were genotyped: Gly374Val (2 POAG patients), Lys500Arg (3 POAG patients) and Tyr453del (5 POAG patients). None of the relatives screened for Gly374Val had the mutation or POAG. The Lys500Arg mutation did not co-segregate with the disease in an affected family. The Tyr453del mutation co-segregated with the disease, but demonstrated incomplete penetrance. POAG patients with the Tyr453del mutation had adult-onset POAG with high intraocular pressures and advanced cupping.
Conclusions: Overall, 3.3% of black South Africans with POAG have a Gly374Val or Tyr453del MYOC mutation. The Tyr453del mutation is incompletely penetrant. That the mutation is necessary but insufficient introduces a counseling dilemma. Mutation screening can, however, identify high-risk individuals who can be monitored to detect early signs of the disease. The Gly374Val mutation is predicted to be damaging to MYOC. The Lys500Arg mutation is predicted to be benign and tolerated. This study has important implications for the management and counseling of black South African patients with POAG and their families. 相似文献
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Background and Purpose
The Kv7 channel activator flupirtine is a clinical analgesic characterized as ‘selective neuronal potassium channel opener’. Flupirtine was found to exert comparable actions at GABAA receptors and Kv7 channels in neurons of pain pathways, but not in hippocampus.Experimental Approach
Expression patterns of GABAA receptors were explored in immunoblots of rat dorsal root ganglia, dorsal horns and hippocampi using antibodies for 10 different subunits. Effects of flupirtine on recombinant and native GABAA receptors were investigated in patch clamp experiments and compared with the actions on Kv7 channels.Key Results
Immunoblots pointed towards α2, α3, β3 and γ2 subunits as targets, but in all γ2‐containing receptors the effects of flupirtine were alike: leftward shift of GABA concentration‐response curves and diminished maximal amplitudes. After replacement of γ2S by δ, flupirtine increased maximal amplitudes. Currents through α1β2δ receptors were more enhanced than those through Kv7 channels. In hippocampal neurons, flupirtine prolonged inhibitory postsynaptic currents, left miniature inhibitory postsynaptic currents (mIPSCs) unaltered and increased bicuculline‐sensitive tonic currents; penicillin abolished mIPSCs, but not tonic currents; concentration‐response curves for GABA‐induced currents were shifted to the left by flupirtine without changes in maximal amplitudes; in the presence of penicillin, maximal amplitudes were increased; GABA‐induced currents in the presence of penicillin were more sensitive towards flupirtine than K+ currents. In dorsal horn neurons, currents evoked by the δ‐preferring agonist THIP (gaboxadol) were more sensitive towards flupirtine than K+ currents.Conclusions and Implications
Flupirtine prefers δ‐containing GABAA receptors over γ‐containing ones and over Kv7 channels.Abbreviations
- aEPSC
- autaptic EPSCs
- aIPSC
- autaptic IPSCs
- BMI
- bicuculline methiodide
- CNQX
- cyano‐2,3‐dihydroxi‐7‐nitroquinoxaline
- DH
- dorsal horn
- DRG
- dorsal root ganglion
- mIPSCs
- miniature IPSCs
- THIP
- 4,5,6,7‐tetrahydroisoxazolo(5,4‐c)pyridin‐3‐ol) hydrochloride (= gaboxadol)
- TTX
- tetrodotoxin
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