Light stimuli produce graded hyperpolarizations of the photoreceptor plasma membrane and an associated decrease in a voltagegated calcium channel conductance that mediates release of glutamate neurotransmitter. The Ca v1.4 channel is thought to be involved in this process. The CACNA1F gene encodes the poreforming subunit of the Cav1.4 channel and various mutations in CACNA1F cause X-linked incomplete congenital stationary night blindness (CSNB2). The molecular mechanism of the pathology underlying the CSNB2 phenotype remains to be established. Recent clinical investigations of a New Zealand family found a severe visual disorder that has some clinical similarities to, but is clearly distinct from, CSNB2. Here, we report investigations into the molecular mechanism of the pathology of this condition. Molecular genetic analyses identified a previously undescribed nucleotide substitution in CACNA1F that is predicted to encode an isoleucine to threonine substitution at CACNA1F residue 745. The I745T CACNA1F allele produced a remarkable approximately ؊30-mV shift in the voltage dependence of Cav1.4 channel activation and significantly slower inactivation kinetics in an expression system. These findings imply that substitution of this wild-type residue in transmembrane segment IIS6 may have decreased the energy required to open the channel. Collectively, these findings suggest that a gain-of-function mechanism involving increased Cav1.4 channel activity is likely to cause the unusual phenotype.
Aims-To estimate the prevalence of Usher syndrome in the city of Birmingham, and to establish a database of patients who have been classified into diVerent clinical subtypes essential for future gene mutation analysis. Methods-Symptomatic cases of Usher syndrome (US) resident in the city of Birmingham in June 1994 were ascertained through multiple sources. Ophthalmic and audiological reassessment together with examination of medical records and patient questionnaires allowed classification of three subtypes, US 1, US 2, and US 3. In addition, family pedigrees were examined and blood was taken from index patients for DNA extraction. Results-In the population aged over 15 years the prevalence was 6.2 per 100 000 population for all US subtypes. The prevalence for US 1 and US 2 was 5.3 per 100 000 population. This is greater than previously reported. In the age group 30-49 years the prevalence approached 1 in 10 000. Clinical classification found 33% US 1, 47% US 2, and 20% US 3. Conclusion-This higher prevalence rate and greater frequency of US 2 and US 3 may reflect a more complete ascertainment. (Br J Ophthalmol 1997;81:46-53) The Usher syndromes (US) are a heterogeneous group of autosomal recessive disorders characterised by congenital hearing loss associated with a progressive pigmentary retinopathy. This association was first described by von Graefe, 1 but it was Charles Usher who first emphasised its familial occurrence.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.