Molecular Screening of<i>Rhodopsin</i>and<i>Peripherin/RDS</i>Genes in Mexican Families with Autosomal Dominant Retinitis Pigmentosa

Matías-Florentino, Margarita; Ayala-Ramírez, Raúl; Graue-Wiechers, Federico; Zenteno, Juan Carlos

doi:10.3109/02713680903283169

Cited by 15 publications

(15 citation statements)

References 38 publications

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“…Multiplex ligation-dependent probe amplification was normal, excluding a copy-number variant on the second allele as an explanation for the phenotype (Supplementary Figure S2 online). An F45L substitution has been reported to be pathogenic in ADRP patients, [29][30][31] however, the pathogenic mechanism could not be identified. 10 Bioinformatic analyses were inconclusive; the residue at site 45 is invariant across vertebrates (Supplementary Figure S1 online) and is found on the outer surface of the first TMD (Figure 2a and Supplementary Figure S3 online), but the Grantham score predicts that the effect of the F45L substitution should be minimal ( Table 2).…”

Section: Validation Of Functional Analysesmentioning

confidence: 99%

Next-generation sequencing in health-care delivery: lessons from the functional analysis of rhodopsin

Davies

Downes

et al. 2012

Genetics in Medicine

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original research articlePurpose: The interpretation of genetic information has always been challenging, but next-generation sequencing produces data on such a vast scale that many more variants of uncertain pathogenicity will be found. We exemplify this issue with reference to human rhodopsin, in which pathogenic mutations can lead to autosomal dominant retinitis pigmentosa.methods: Rhodopsin variants, with unknown pathogenicity, were found in patients by next-generation and Sanger sequencing and a multidisciplinary approach was used to determine their functional significance.Results: Four variants in rhodopsin were identified: F45L, P53R, R69H, and M39R, with the latter two substitutions being novel. We investigated the cellular transport and photopigment function of all four human substitutions and found that the F45L and R69H variants behave like wild-type and are highly unlikely to be pathogenic. By contrast, P53R (a de novo change) and M39R were retained in the endoplasmic reticulum with significantly reduced functionality and are clearly pathogenic.conclusion: Potential pathogenicity of variants requires careful assessment using clinical, genetic, and functional data. We suggest that a multidisciplinary pathway of assessment, using several functional assays, will be required if next-generation sequencing is to be used effectively, reliably, and safely in the clinical environment. 2012:14(11):891-899 Genet Med

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Section: Validation Of Functional Analysesmentioning

confidence: 99%

Next-generation sequencing in health-care delivery: lessons from the functional analysis of rhodopsin

Davies

Downes

et al. 2012

Genetics in Medicine

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“…Hence, we focused on the quantitative comparison of ERG responses. Ruther et al (11) and Matias-Florentino et al (59) have reported cases of 30-and 36-year-old S186W-affected patients, respectively, who had either barely recordable or completely abolished ERGs. However, Fishman et al (74) reported that D190N-affected patients at ages of 36 and 80 years had ERGs with delayed but still detectable responses.…”

Section: Thermal Stability Of Rhodopsin and Progression Of Rpmentioning

confidence: 99%

“…Experiments on the nonpathogenic S186A mutation revealed that it increases the rate of thermal decay by 3-fold compared with wild type (WT) (46) and increases the rates of thermal isomerization and hydrolysis of SB by 2 orders of magnitude at 55°C (43,44). However, the pathogenic S186W mutant has not been characterized at the molecular level, although clinical studies suggest a severe phenotype (11,59).…”

mentioning

confidence: 99%

Thermal Stability of Rhodopsin and Progression of Retinitis Pigmentosa

Liu¹,

Liu²,

Mehrotra³

et al. 2013

Journal of Biological Chemistry

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Background: The S186W mutation in rhodopsin causes retinitis pigmentosa (RP). Results: The mutation expedites thermal isomerization and hydrolysis of the Schiff base by orders of magnitude. Conclusion: Lower thermal stability could link to higher levels of dark noise, associated with RP's early symptom, night blindness. Significance: Further quantitative kinetic studies could potentially establish a correlation between thermal stability and RP progression.

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“…Davies and colleagues provided a good example of this in 2012, when they analyzed rod opsin variants using a combination of Sanger sequencing, NGS, genetic and bioinformatics analyses, and functional assays [46,47]. This study demonstrated that some previously reported mutations, such as Phe45Leu [62][63][64], showed an unclear prediction of pathogenicity, but did not appear to have a dysfunctional phenotype. By contrast, a Met39Arg substitution, which was not highly predicted to be pathogenic using bioinformatics analyses, clearly showed trafficking and functional defects (Figure 3) [46,47].…”

Section: Variants Of Unknown Significance Incidental Findings and Bioimentioning

confidence: 88%

Challenges Using Diagnostic Next-Generation Sequencing in the Clinical Environment for Inherited Retinal Disorders

Davies

2014

Personalized Medicine

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Visual impairment, and in particular the inherited retinopathies, is a significant problem worldwide. Many disorders are progressive so their early and accurate detection is crucial to the development and application of appropriate disease management and treatment strategies, some of which are currently being tested in clinical trials. Over the past few decades, the identification of genetic causes that mediate many inherited diseases has largely been based on traditional 'Sanger sequencing' and microchip approaches that are expensive and time consuming. However, with the advent of next-generation sequencing it is now possible to apply high-throughput technologies to the clinical arena and sequence the entire exome or genome of an affected individual. Despite the potential for a paradigm shift in the clinical diagnosis of retinal disease, it may prove difficult to interpret and confirm the pathogenicity of any variants discovered by next-generation sequencing pipelines. In this review, I examine the application of next-generation sequencing to inherited retinal disorders and discuss current limitations and future perspectives.

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Molecular Screening ofRhodopsinandPeripherin/RDSGenes in Mexican Families with Autosomal Dominant Retinitis Pigmentosa

Cited by 15 publications

References 38 publications

Next-generation sequencing in health-care delivery: lessons from the functional analysis of rhodopsin

Next-generation sequencing in health-care delivery: lessons from the functional analysis of rhodopsin

Thermal Stability of Rhodopsin and Progression of Retinitis Pigmentosa

Challenges Using Diagnostic Next-Generation Sequencing in the Clinical Environment for Inherited Retinal Disorders

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