Mutational Screening of the<i>RP2</i>and<i>RPGR</i>Genes in Spanish Families with X-Linked Retinitis Pigmentosa

Garcia‐Hoyos, Maria; Garcı́a-Sandoval, Blanca; Cantalapiedra, Diego; Riveiro, Rosa; Lorda‐Sánchez, Isabel; Trujillo-Tiebas, María José; Alba, Marta Rodríguez de; Millán, José María; Baiget, M.; Ramos, Carlos; Ayuso, Carmen

doi:10.1167/iovs.06-0323

Cited by 20 publications

(12 citation statements)

References 29 publications

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“…In order to assess the potential implication of ABCA4 mutant alleles in autosomal recessive retinitis pigmentosa, 75 Spanish arRP patients with or without identified variants in ABCA4 after screening with the ABCR400 array, or those who were excluded by haplotype analysis, were further tested for mutations in other RP-related genes by genotyping with the Asper Biotech arRP microarray, 19 homozygosity mapping, or whole exome sequencing (Avila-Fernandez 2012; submitted).…”

Section: Methodsmentioning

confidence: 99%

Outcome of ABCA4 Disease-Associated Alleles in Autosomal Recessive Retinal Dystrophies

et al. 2013

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Objective To provide a comprehensive overview of all detected mutations in the ABCA4 gene in Spanish families with autosomal recessive retinal disorders, including Stargardt disease (arSTGD), cone-rod dystrophy (arCRD), and retinitis pigmentosa (arRP). Also, to assess genotype-phenotype correlation and disease progression in 10 years by considering type of variants and age of onset. Design Case series. Participants A total of 420 unrelated Spanish families: 259 arSTGD, 86 arCRD and 75 arRP. Methods Spanish families were analysed through a combination of ABCR400 genotyping microarray, denaturing High-Performance Liquid Chromatography (dHPLC) and High Resolution Melting (HRM) scanning. Direct sequencing was used as confirmation technique for the identified variants. Screening by Multiple Ligation Probe Analysis (MLPA) was used in order to detect possible large deletions or insertions in the ABCA4 gene. Selected families were further analysed by Next Generation Sequencing (NGS). Main Outcome Measures DNA sequence variants, mutation detection rates, haplotypes, age of onset, central or peripheral vision loss, night blindness. Results Overall, we detected 70.5% and 36.6% of all expected ABCA4 mutations in arSTGD and arCRD patient cohorts, respectively. In the fraction of the cohort where the ABCA4 gene was completely sequenced the detection rates reached 73.6% for STGD and 66.7% for CRD. However, the frequency of possibly pathogenic ABCA4 alleles in arRP families was only slightly higher to that in the general population. Moreover, in some families mutations in other known arRP genes segregated with the disease phenotype. Conclusions An increasing understanding of causal ABCA4 alleles in arSTGD and arCRD facilitates disease diagnosis and prognosis and is also paramount in selecting patients for emerging clinical trials of therapeutic interventions. As ABCA4-associated diseases are evolving retinal dystrophies, assessment of age of onset, accurate clinical diagnosis and genetic testing are crucial. We suggest that ABCA4 mutations may be associated with an RP-like phenotype often as a consequence of severe (null) mutations and/or in cases of long-term, advanced disease. Patients with “classical” arRP phenotypes, especially from the onset of the disease, should be first screened for mutations in known arRP genes and not ABCA4.

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Section: Methodsmentioning

confidence: 99%

Outcome of ABCA4 Disease-Associated Alleles in Autosomal Recessive Retinal Dystrophies

et al. 2013

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“…One was reported by Chakarova et al [2006], one by Sullivan et al [2006], seven by Garcia-Hoyos et al [2006], and 26 by Pelletier et al [2007].…”

Section: Note Added In Proofmentioning

confidence: 97%

RPGRmutation analysis and disease: an update

et al. 2007

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Mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene are the most common single cause of retinitis pigmentosa, accounting for up to 15 to 20% of cases in Caucasians. A total of 240 different RPGR mutations have been reported, including 24 novel ones in this work, which are associated with X-linked retinitis pigmentosa (XLRP) (95%), cone, cone-rod dystrophy, or atrophic macular atrophy (3%), and syndromal retinal dystrophies with ciliary dyskinesia and hearing loss (2%). All disease-causing mutations occur in one or more RPGR isoforms containing the carboxyl-terminal exon open reading frame 15 (ORF15), which are widely expressed but show their highest expression in the connecting cilia of rod and cone photoreceptors. Of reported RPGR mutations, 55% occur in a glutamic acid-rich domain within exon ORF15, which accounts for only 31% of the protein. RPGR forms complexes with a variety of other proteins and appears to have a role in microtubular organization and transport between photoreceptor inner and outer segments.

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“…This 15-exon transcript is highly expressed in the retina and is mutated in 30% to 63% of males with XLRP. 15,[23][24][25][26][27][28][29][30] Mutations in RPGR are associated with XLRP, as well as with X-linked cone-dystrophy (COD), 29,31 cone rod dystrophy (CORD), 32,33 and an atrophic form of macular degeneration. 34 Patients with COD or CORD may present with decreased visual acuity, central vision loss, and decreased color vision.…”

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Mutations inRPGRandRP2Account for 15% of Males with Simplex Retinal Degenerative Disease

Branham

Othman

Brumm

et al. 2012

Invest. Ophthalmol. Vis. Sci.

108

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PURPOSE.To determine the proportion of male patients presenting simplex retinal degenerative disease (RD: retinitis pigmentosa [RP] or cone/cone-rod dystrophy [COD/CORD]) with mutations in the X-linked retinal degeneration genes RPGR and RP2.METHODS. Simplex males were defined as patients with no known affected family members. Patients were excluded if they had a family history of parental consanguinity. Blood samples from a total of 214 simplex males with a diagnosis of retinal degeneration were collected for genetic analysis. The patients were screened for mutations in RPGR and RP2 by direct sequencing of PCR-amplified genomic DNA. RESULTS.We identified pathogenic mutations in 32 of the 214 patients screened (15%). Of the 29 patients with a diagnosis of COD/CORD, four mutations were identified in the ORF15 mutational hotspot of the RPGR gene. Of the 185 RP patients, three patients had mutations in RP2 and 25 had RPGR mutations (including 12 in the ORF15 region).CONCLUSIONS. This study represents mutation screening of RPGR and RP2 in the largest cohort, to date, of simplex males affected with RP or COD/CORD. Our results demonstrate a substantial contribution of RPGR mutations to retinal degenerations, and in particular, to simplex RP. Based on our findings, we suggest that RPGR should be considered as a first tier gene for screening isolated males with retinal degeneration. (Invest Ophthalmol Vis Sci. 2012;53:8232-8237)

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Mutational Screening of theRP2andRPGRGenes in Spanish Families with X-Linked Retinitis Pigmentosa

Abstract: In this cohort of XLRP families, as has happened in previous studies, RP3 also seems to be the most prevalent form of XLRP, and, based on the results, the authors propose a four-step protocol for molecular diagnosis of XLRP families.

Cited by 20 publications

References 29 publications

Outcome of ABCA4 Disease-Associated Alleles in Autosomal Recessive Retinal Dystrophies

Outcome of ABCA4 Disease-Associated Alleles in Autosomal Recessive Retinal Dystrophies

RPGRmutation analysis and disease: an update

Mutations inRPGRandRP2Account for 15% of Males with Simplex Retinal Degenerative Disease

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