A novel mutation within the rhodopsin gene (Thr-94-Ile) causing autosomal dominant congenital stationary night blindness

al-Jandal, Najma; Farrar, G. Jane; Kiang, Anna‐Sophia; Humphries, Marian M.; Bannon, Noreen; Findlay, John B. C.; Humphries, Peter; Kenna, Paul F.

doi:10.1002/(sici)1098-1004(1999)13:1<75::aid-humu9>3.0.co;2-4

Cited by 89 publications

(47 citation statements)

References 19 publications

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“…91,92 By contrast, the T94I variant, which shows a normal conversion into Meta II, [85][86][87] does not cause retinal degeneration. 90 These observations support the hypothesis that abnormal rhodopsin photoactivity, characterized by MI-like intermediates as in our study, contributes to the RP phenotype. Further studies are needed to define these photointermediates in greater detail, ideally in intact outer segments, and to explore the cellular pathways by which they cause degeneration of the rod cell.…”

Section: Discussionsupporting

confidence: 90%

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Molecular Mechanisms of Rhodopsin Retinitis Pigmentosa and the Efficacy of Pharmacological Rescue

Krebs

Holden

Joshi

et al. 2010

Journal of Molecular Biology

118

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Section: Discussionsupporting

confidence: 90%

“…G90D, T94I, A292E, and A295V rhodopsin exhibit altered photoactivity [82][83][84][85][86][87][88] and cause congenital stationary night blindness (CSNB), 82,88,89,90 a rod-specific disease with little or no retinal degeneration. The mutant proteins are thought to be synthesized normally in rod cells.…”

Section: Discussionmentioning

confidence: 99%

Molecular Mechanisms of Rhodopsin Retinitis Pigmentosa and the Efficacy of Pharmacological Rescue

Krebs

Holden

Joshi

et al. 2010

Journal of Molecular Biology

118

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“…enhanced rate of thermal isomerization due to lowered activation energy caused by the mutation (12,13). More recently, a third mutation associated with CNB, T94I, in the second transmembrane helix of rhodopsin, has been described (14). The study of mutations associated with CNB can provide important information about the differences between RP and CNB at the molecular level.…”

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confidence: 99%

Unusual Thermal and Conformational Properties of the Rhodopsin Congenital Night Blindness Mutant Thr-94 → Ile

Ramon

Valle

Garriga

2003

Journal of Biological Chemistry

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Naturally occurring point mutations in the opsin gene cause the retinal diseases retinitis pigmentosa and congenital night blindness. Although these diseases involve similar mutations in very close locations in rhodopsin, their progression is very different, with retinitis pigmentosa being severe and causing retinal degeneration. We report on the expression and characterization of the recently found T94I mutation associated with congenital night blindness, in the second transmembrane helix or rhodopsin, and mutations at the same site. T94I mutant rhodopsin folded properly and was able to bind 11-cis-retinal to form chromophore, but it showed a blue-shifted visible band at 478 nm and reduced molar extinction coefficient. Furthermore, T94I showed dramatically reduced thermal stability, extremely long lived metarhodopsin II intermediate, and highly increased reactivity toward hydroxylamine in the dark, when compared with wild type rhodopsin. The results are consistent with the location of Thr-94 in close proximity to Glu-113 counterion in the vicinity of the Schiff base linkage and suggest a role for this residue in maintaining the correct dark inactive conformation of the receptor. The reported results, together with previously published data on the other two known congenital night blindness mutants, suggest that the molecular mechanism underlying this disease may not be structural misfolding, as proposed for retinitis pigmentosa mutants, but abnormal functioning of the receptor by decreased thermal stability and/or constitutive activity.Naturally occurring mutations in rhodopsin (most of them single amino acid replacements) are associated with retinal disease. Most of these are the cause of retinitis pigmentosa (RP), 1 a group of inherited retinal degenerative diseases (1-3) that leads to blindness by causing photoreceptor cell death (4). Over 100 mutations have been found to date in the opsin gene associated with RP, most of them being inherited as an autosomal dominant trait (1). These are located in all the three domains of rhodopsin, namely the intradiscal, the transmembrane, and the cytoplasmic domains of the protein (5). Mutations in the transmembrane and intradiscal domains of rhodopsin that cause RP have been shown to cause misfolding of the mutant proteins (6 -8). Only a very small number of mutations have been associated with the retinal disease characterized by a congenital night blindness (CNB) phenotype. CNB appears to be a stable condition that does not seem to cause photoreceptor degeneration resulting mainly in night vision impairment. Two of these mutations were previously studied, namely G90D (9) and A292E (10) in transmembrane helices II and VII of rhodopsin, respectively. The mechanism of action of the G90D and A292E mutations was proposed to be persistent activation of the phototransduction pathway by constitutive activity of the mutant proteins (9 -11). Another possible explanation for the observed G90D mutant phenotype has been proposed, i.e. enhanced rate of thermal isomerization due to lo...

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“…[1,2,4-10] The autosomal dominant forms are caused by mutations in the RHO (CSNBAD1, MIM #610445), PDE6B (CSNBAD2, #163500) and GNAT1 (CSNBAD3, #610444) genes. [5][6][7] The X-linked and autosomal recessive forms are further divided into complete and incomplete sub-types on the basis of electroretinogram findings of markedly reduced or absent rod b-waves but retained cone function in the complete type and residual rod function with reduced cone amplitudes in the incomplete form. [3] The autosomal recessive complete forms are associated with mutations in GRM6 (CSNB1B, MIM #257270) and TRPM1 (CSNB1C, MIM #613216) and incomplete forms with CABP4 (CSNB2B, MIM #610427) genes.…”

Section: Discussionmentioning

confidence: 99%

A Novel NYX Mutation Associated with X-Linked Congenital Stationary Night Blindness in a New Zealand Family

Pradhan¹,

Sharp²,

Mora³

et al. 2011

J Clin Exp Ophthalmol

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A novel mutation within the rhodopsin gene (Thr-94-Ile) causing autosomal dominant congenital stationary night blindness

Cited by 89 publications

References 19 publications

Molecular Mechanisms of Rhodopsin Retinitis Pigmentosa and the Efficacy of Pharmacological Rescue

Molecular Mechanisms of Rhodopsin Retinitis Pigmentosa and the Efficacy of Pharmacological Rescue

Unusual Thermal and Conformational Properties of the Rhodopsin Congenital Night Blindness Mutant Thr-94 → Ile

A Novel NYX Mutation Associated with X-Linked Congenital Stationary Night Blindness in a New Zealand Family

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