Truncation of retinoschisin protein associated with a novel splice site mutation in the RS1 gene

Balász Lesch, Viktória Szabó, Melinda Kánya, Balázs Varsányi, G. M. Somfai, János Hargitai, Rita Vámos, Orsolya Fiedler, A. Farkas

Research output: Contribution to journalArticle

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Abstract

Purpose: To present the ocular findings of a Hungarian family with X-linked juvenile retinoschisis (XLRS) and to reveal a novel putative splice mutation leading to serious truncation of retinoschisin (RS1) protein. Our genetic results were compared to a mouse model of XLRS. Methods: Complete ophthalmic examinations were performed on five members (two male patients, two female carriers, and one healthy fraternal male twin) of the family. The examinations included optical coherence tomography (OCT) and full-field and multifocal electroretinography (mfERG). OCT and ERG results were compared to the normative database of our laboratory. All exons and the flanking intronic regions of the RS1 gene were amplified by polymerase chain reaction and directly sequenced in all family members and in 50 male controls. Results: Typical microcystic foveal changes were found on fundoscopy and OCT in two male patients. Large foveal and smaller perifoveal cysts were detected by OCT in the inner nuclear layer and another deeper retinal cleavage in the photoreceptor layer. The standard combined b-wave amplitudes and b/a amplitude ratios of full-field ERGs of the male patients were decreased compared with controls, but the typical "negative-type" ERG was not observed. The amplitudes of mfERGs were reduced in all rings but mainly in the central part of the examined retina. Implicit times were delayed across almost the whole testing field. Female carriers and the healthy fraternal twin brother were without any symptoms and had normal clinical examination results, but the implicit times of female carriers were delayed in all rings. DNA sequence analyses revealed a novel putative splice mutation (c.78+1G>C) in the splice donor site of intron 2 in RS1 of two male patients and two female carriers. Mutations were absent in the 50 control samples. Conclusions: Male patients exhibited typical bilateral foveal retinoschisis in two retinal layers and characteristic ERG changes. The inheritance of the novel putative splice mutation (c.78+1G>C) followed the classic inheritance of an X-linked recessive disease in two male patients and two female obligate carriers. There are two possible ways the c.78+1G>C splice site mutation may lead to frameshift and introduce a premature termination codon at the beginning of exon 3: after activation of the next cryptic splice site by a 10 bp insertion or after exon skipping by a 26 bp deletion. The splice site mutation in the second intron of RS1 identified in these XLRS patients is practically identical to the N-ethyl-N-nitrosourea (ENU) induced splice site mutation in the mouse model of XLRS described by the Tennessee Mouse Genome Consortium. The genetic findings of the mutant mouse model confirm and support our human results.

Original languageEnglish
Pages (from-to)1549-1558
Number of pages10
JournalMolecular Vision
Volume14
Publication statusPublished - Aug 25 2008

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Retinoschisis
Mutation
Optical Coherence Tomography
Genes
Proteins
Dizygotic Twins
Exons
RNA Splice Sites
Introns
Ethylnitrosourea
Electroretinography
X-Linked Genes
Nonsense Codon
DNA Sequence Analysis
Retina
Cysts
Siblings
Genome
Databases
Polymerase Chain Reaction

ASJC Scopus subject areas

  • Ophthalmology

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Truncation of retinoschisin protein associated with a novel splice site mutation in the RS1 gene. / Lesch, Balász; Szabó, Viktória; Kánya, Melinda; Varsányi, Balázs; Somfai, G. M.; Hargitai, János; Vámos, Rita; Fiedler, Orsolya; Farkas, A.

In: Molecular Vision, Vol. 14, 25.08.2008, p. 1549-1558.

Research output: Contribution to journalArticle

Lesch, B, Szabó, V, Kánya, M, Varsányi, B, Somfai, GM, Hargitai, J, Vámos, R, Fiedler, O & Farkas, A 2008, 'Truncation of retinoschisin protein associated with a novel splice site mutation in the RS1 gene', Molecular Vision, vol. 14, pp. 1549-1558.
Lesch B, Szabó V, Kánya M, Varsányi B, Somfai GM, Hargitai J et al. Truncation of retinoschisin protein associated with a novel splice site mutation in the RS1 gene. Molecular Vision. 2008 Aug 25;14:1549-1558.
Lesch, Balász ; Szabó, Viktória ; Kánya, Melinda ; Varsányi, Balázs ; Somfai, G. M. ; Hargitai, János ; Vámos, Rita ; Fiedler, Orsolya ; Farkas, A. / Truncation of retinoschisin protein associated with a novel splice site mutation in the RS1 gene. In: Molecular Vision. 2008 ; Vol. 14. pp. 1549-1558.
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AU - Szabó, Viktória

AU - Kánya, Melinda

AU - Varsányi, Balázs

AU - Somfai, G. M.

AU - Hargitai, János

AU - Vámos, Rita

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N2 - Purpose: To present the ocular findings of a Hungarian family with X-linked juvenile retinoschisis (XLRS) and to reveal a novel putative splice mutation leading to serious truncation of retinoschisin (RS1) protein. Our genetic results were compared to a mouse model of XLRS. Methods: Complete ophthalmic examinations were performed on five members (two male patients, two female carriers, and one healthy fraternal male twin) of the family. The examinations included optical coherence tomography (OCT) and full-field and multifocal electroretinography (mfERG). OCT and ERG results were compared to the normative database of our laboratory. All exons and the flanking intronic regions of the RS1 gene were amplified by polymerase chain reaction and directly sequenced in all family members and in 50 male controls. Results: Typical microcystic foveal changes were found on fundoscopy and OCT in two male patients. Large foveal and smaller perifoveal cysts were detected by OCT in the inner nuclear layer and another deeper retinal cleavage in the photoreceptor layer. The standard combined b-wave amplitudes and b/a amplitude ratios of full-field ERGs of the male patients were decreased compared with controls, but the typical "negative-type" ERG was not observed. The amplitudes of mfERGs were reduced in all rings but mainly in the central part of the examined retina. Implicit times were delayed across almost the whole testing field. Female carriers and the healthy fraternal twin brother were without any symptoms and had normal clinical examination results, but the implicit times of female carriers were delayed in all rings. DNA sequence analyses revealed a novel putative splice mutation (c.78+1G>C) in the splice donor site of intron 2 in RS1 of two male patients and two female carriers. Mutations were absent in the 50 control samples. Conclusions: Male patients exhibited typical bilateral foveal retinoschisis in two retinal layers and characteristic ERG changes. The inheritance of the novel putative splice mutation (c.78+1G>C) followed the classic inheritance of an X-linked recessive disease in two male patients and two female obligate carriers. There are two possible ways the c.78+1G>C splice site mutation may lead to frameshift and introduce a premature termination codon at the beginning of exon 3: after activation of the next cryptic splice site by a 10 bp insertion or after exon skipping by a 26 bp deletion. The splice site mutation in the second intron of RS1 identified in these XLRS patients is practically identical to the N-ethyl-N-nitrosourea (ENU) induced splice site mutation in the mouse model of XLRS described by the Tennessee Mouse Genome Consortium. The genetic findings of the mutant mouse model confirm and support our human results.

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