A novel constitutively active rhodopsin mutation (p.Ala295Val) causes autosomal dominant CSNB

¹ Division of Medical Molecular Genetics and Gene Diagnostics, University of Zurich, Institute of Medical Genetics, Zurich, Switzerland; INSERM, U592, Universit� Pierre et Marie Curie6, Institut de la Vision, Paris, France
² Department of Vision Sciences, University of Alabama at Birmingham, Birmingham, Alabama, United States
³ Department of Ophthalmology, University Hospital Basel, Basel, Switzerland
⁴ Division of Medical Molecular Genetics and Gene Diagnostics, Institute of Medical Genetics, University of Zurich, Schorenstrasse 16, Schwerzenbach, 8603, Switzerland; Department of Biology, ETH, Zurich, Switzerland
⁵ Swiss Epilepsy Centre, Zurich, Switzerland
⁶ Division of Medical Molecular Genetics and Gene Diagnostics, Institute of Medical Genetics, University of Zurich, Schorenstrasse 16, Schwerzenbach, 8603, Switzerland

^* To whom correspondence should be addressed. E-mail: christina.zeitz{at}inserm.fr.

	Abstract

Purpose. Mutations in RHO, PDE6B and GNAT1 can lead to autosomal dominant congenital stationary night blindness (adCSNB). We aimed to identify the genetic defect in a large Swiss family affected with adCSNB and to investigate the pathogenic mechanism of the mutation. Methods. Two affected cousins of a large Swiss family were examined clinically with standard methods, funduscopy, EOG, ERG and dark adaptometry. Twelve family members were screened for mutations in RHO. The ability of mutant rhodopsin to constitutively activate transducin was monitored by measuring the catalytic exchange of bound GDP for radiolabeled [35S]GTPS in transducin. Results. We identified a novel mutation in RHO (c.884C>T, p.Ala295Val) in patients with adCSNB. They had full vision under photopic conditions, showed no fundus abnormalities, revealed EOG results in the normal range but presented night blindness with an altered scotopic ERG. In the presence of 11-cis retinal the mutant rhodopsin is inactive, similar to wild type, responding only when exposed to light. However, in the absence of 11-cis-retinal, unlike wild type opsin, the mutant opsin constitutively activates transducin. Conclusions. Our study adds a fourth rhodopsin mutation associated with CSNB. Although the phenotype of autosomal dominant CSNB may vary slightly in patients showing mutations in RHO, PDE6B or GNAT1, the disease course seems to be stationary with only scotopic vision being affected. Our data indicate that the mutant opsin is able to constitutively activate transducin, which is a consistent and common feature of all four CSNB-associated rhodopsin mutations reported to date.

Key Words: rhodopsin, electroretinography, molecular biology

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