A heterozygous novel C253Y mutation in the highly conserved cysteine residues of ROM1 gene is the cause of retinitis pigmentosa in a Spanish family?

Reig, Carlos Padrós i; Martinez-Gimeno, María; Carballo, Miguel

doi:10.1002/1098-1004(200009)16:3<278::aid-humu29>3.0.co;2-g

Cited by 7 publications

(5 citation statements)

References 3 publications

(3 reference statements)

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“…Mir et al, 1997;Reig et al, 2000). An additional ROM1 stop-gain variant was identified in another individual in our cohort, c.339dup p.(Leu114Alafs*18), which was previously reported in literature as "most likely not pathogenic"(Boulanger-Scemama et al, 2015).…”

supporting

confidence: 75%

“…For noncanonical splice site variants, near‐exon variants and DIVs, in silico tools Splice Site Finder‐like (Zhang, 1998 ), MaxEntScan (Yeo & Burge, 2004 ), NNSPLICE (Reese et al, 1997 ) and GeneSplicer (Pertea et al, 2001 ) were used in Alamut Visual software version 2.13 (Interactive Biosoftware) to predict the impact on splicing, using parameters described by Fadaie et al ( 2019 ), and ESEfinder (Cartegni et al, 2003 ) to predict effects on exon splicing enhancers (ESEs). SpliceAI (Jaganathan et al, 2019 ) was used via the BROAD Institute web interface tool ( https://spliceailookup.broadinstitute.org/ #) to further predict splicing effects, using a 10,000‐bp (5000‐bp upstream and 5000‐bp downstream) window.…”

Section: Methodsmentioning

confidence: 99%

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Using single molecule Molecular Inversion Probes as a cost‐effective, high‐throughput sequencing approach to target all genes and loci associated with macular diseases

et al. 2022

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Macular degenerations (MDs) are a subgroup of retinal disorders characterized by central vision loss. Knowledge is still lacking on the extent of genetic and nongenetic factors influencing inherited MD (iMD) and age-related MD (AMD) expression.Single molecule Molecular Inversion Probes (smMIPs) have proven effective in sequencing the ABCA4 gene in patients with Stargardt disease to identify associated coding and noncoding variation, however many MD patients still remain genetically unexplained. We hypothesized that the missing heritability of MDs may be revealed by smMIPs-based sequencing of all MD-associated genes and risk factors. Using 17,394 smMIPs, we sequenced the coding regions of 105 iMD and AMD-associated genes and noncoding or regulatory loci, known pseudo-exons, and the mitochondrial genome in two test cohorts that were previously screened for variants in ABCA4.Following detailed sequencing analysis of 110 probands, a diagnostic yield of 38% was observed. This established an ''MD-smMIPs panel," enabling a genotype-first approach in a high-throughput and cost-effective manner, whilst achieving uniform and high coverage across targets. Further analysis will identify known and novel

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supporting

confidence: 75%

Section: Methodsmentioning

confidence: 99%

Using single molecule Molecular Inversion Probes as a cost‐effective, high‐throughput sequencing approach to target all genes and loci associated with macular diseases

et al. 2022

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“…Variants in ROM1 and the implication in IRDs are not completely understood. Heterozygous ROM1 variants have been reported with heterozygous PRPH2 variants to cause digenic RP [47] in addition to few putative associations of heterozygous ROM1 variants with adRP with incomplete penetrance [48,49]. An additional ROM1 stop-gain variant was identified in another individual in our cohort, c.339dup; p.(Leu114Alafs*18), which was previously reported in literature as ''most likely not pathogenic'' [50].…”

Section: Novel Findingssupporting

confidence: 63%

Using single molecule Molecular Inversion Probes as a cost-effective, high-throughput sequencing approach to target all genes and loci associated with macular diseases

Hitti‐Malin

Dhaenens

Panneman

et al. 2022

Preprint

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BackgroundMacular diseases (MDs) are a subgroup of retinal disorders characterized by central vision loss that represent a major cause of vision impairment. Despite the identification of numerous genes associated with inherited MD (iMD) and risk factors associated with age-related MD (AMD), the extent of genetic and non-genetic factors that influence the expression of MD is still not fully explained. Single molecule Molecular Inversion Probes (smMIPs) have proven effective in sequencing the ABCA4 gene in patients with Stargardt disease in a cost-effective manner to identify associated coding and non-coding variation, however a large portion of patients with MDs still remain genetically unexplained.MethodsFor MD patients, we hypothesized that the missing heritability may be revealed by smMIPs-based sequencing of all MD-associated genes and risk factors. We used 17,394 smMIPs to sequence the coding regions of 105 genes and non-coding or regulatory loci associated with iMD and AMD, known pseudo-exons, and the mitochondrial genome in two test cohorts that had previously been screened for variants in the entire ABCA4 gene.ResultsSequencing of 379 probands achieved an average nucleotide coverage of 431× across all targets. Following detailed sequencing analysis of 110 probands, a diagnostic yield of 38% was observed. This established an ‘‘MD-smMIPs panel’’ that allows a genotype-first approach in a high-throughput and cost-effective manner, whilst achieving uniform and high coverage across targets.ConclusionsFurther analysis will identify known and novel variants in MD-associated genes to offer an accurate clinical diagnosis to patients and their families. Furthermore, this will reveal new genetic associations for MD and potential genetic overlaps between iMD and AMD.

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“…While evidence that ROM1 mutations alone may cause human visual pathology is limited (Bascom et al, 1995 ;Sakuma et al, 1995 ;Reig et al, 2000 ), photoreceptors of Rom1 -/mice eventually degenerate (Clarke et al, 2000 ). We propose that the delay in disc enclosure is the primary defect underlying this degeneration.…”

Section: Discussionmentioning

confidence: 83%

“…Around 200 mutations of PRPH2 are shown to cause a heterogeneous set of inherited retinal diseases, including retinitis pigmentosa, cone-rod dystrophy and macular dystrophies (Landrum et al, 2018 ;Peeters et al, 2021 ). Yet, mutations in ROM1 typically cause digenic retinitis pigmentosa in conjunction with mutations in PRPH2 (Kajiwara et al, 1994 ;Dryja et al, 1997 ), except for a handful of reports of mutations in ROM1 in patients without accompanying PRPH2 mutations (Bascom et al, 1995 ;Sakuma et al, 1995 ;Reig et al, 2000 ). With regard to animal models, the Prph2 knockout mouse, commonly known as the rds mouse, has a complete failure of outer segment formation (Cohen, 1983 ;Jansen and Sanyal, 1984 ), while the Rom1 knockout mouse forms outer segments with relatively minor structural abnormalities (Clarke et al, 2000 ).…”

Section: Introductionmentioning

confidence: 99%

ROM1 is redundant to PRPH2 as a molecular building block of photoreceptor disc rims

Lewis,

Makia,

Castillo

et al. 2023

eLife

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Visual signal transduction takes place within a stack of flattened membranous “discs” enclosed within the light-sensitive photoreceptor outer segment. The highly curved rims of these discs, formed in the process of disc enclosure, are fortified by large hetero-oligomeric complexes of two homologous tetraspanin proteins, PRPH2 (a.k.a. peripherin-2 or rds) and ROM1. While mutations in PRPH2 affect the formation of disc rims, the role of ROM1 remains poorly understood. In this study, we found that the knockout of ROM1 causes a compensatory increase in the disc content of PRPH2. Despite this increase, discs of ROM1 knockout mice displayed a delay in disc enclosure associated with a large diameter and lack of incisures in mature discs. Strikingly, further increasing the level of PRPH2 rescued these morphological defects. We next showed that disc rims are still formed in a knockin mouse in which the tetraspanin body of PRPH2 was replaced with that of ROM1. Together, these results demonstrate that, despite its contribution to the formation of disc rims, ROM1 can be replaced by an excess of PRPH2 for timely enclosure of newly forming discs and establishing normal outer segment structure.

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A heterozygous novel C253Y mutation in the highly conserved cysteine residues of ROM1 gene is the cause of retinitis pigmentosa in a Spanish family?

Cited by 7 publications

References 3 publications

Using single molecule Molecular Inversion Probes as a cost‐effective, high‐throughput sequencing approach to target all genes and loci associated with macular diseases

Using single molecule Molecular Inversion Probes as a cost‐effective, high‐throughput sequencing approach to target all genes and loci associated with macular diseases

Using single molecule Molecular Inversion Probes as a cost-effective, high-throughput sequencing approach to target all genes and loci associated with macular diseases

ROM1 is redundant to PRPH2 as a molecular building block of photoreceptor disc rims

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