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Contribution of SNRNP200 sequence variations to retinitis pigmentosa.

ABSTRACT: PURPOSE: Mutations in the SNRNP200 gene have been reported to cause autosomal dominant retinitis pigmentosa (adRP). In this study, we evaluate the mutation profile of SNRNP200 in a cohort of southern Chinese RP patients. METHODS: Twenty adRP patients from 11 families and 165 index patients with non-syndromic RP with mixed inheritance patterns were screened for mutations in the mutation hotspots of SNRNP200. These included exons 12-16, 22-32, and 38-45, which covered the two helicase ATP-binding domains in DEAD-box and two sec-63 domains. The targeted regions were amplified by polymerase chain reaction and analyzed by direct DNA sequencing, followed by in silico analyses. RESULTS: Totally 26 variants were identified, 18 of which were novel. Three non-synonymous variants (p.C502R, p.R1779H and p.I698V) were found exclusively in patients. Two of them, p.C502R and p.R1779H, were each identified in one simplex RP patient, whereas p.I698V occurred in one patient with unknown inheritance pattern. All three residues are highly conserved in SNRNP200 orthologs. Nevertheless, only p.C502R and p.R1779H were predicted to affect protein function by in silico analyses, suggesting these two variants are likely to be disease-causing mutations. Notably, all mutations previously identified in other study populations were not detected in this study. CONCLUSIONS: Our results reveal a distinct mutation profile of the SNRNP200 gene in a southern Chinese cohort of RP patients. The identification of two novel candidate mutations in two respective patients affirmed that SNRNP200 contributes to a proportion of overall RP.

SUBMITTER: Zhang X

PROVIDER: S-EPMC3806570 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Contribution of SNRNP200 sequence variations to retinitis pigmentosa.

Zhang X X Lai T Y Y TY Chiang S W Y SW Tam P O S PO Liu D T L DT Chan C K M CK Pang C P CP Zhao C C Chen L J LJ

Eye (London, England) 20130726 10

<h4>Purpose</h4>Mutations in the SNRNP200 gene have been reported to cause autosomal dominant retinitis pigmentosa (adRP). In this study, we evaluate the mutation profile of SNRNP200 in a cohort of southern Chinese RP patients.<h4>Methods</h4>Twenty adRP patients from 11 families and 165 index patients with non-syndromic RP with mixed inheritance patterns were screened for mutations in the mutation hotspots of SNRNP200. These included exons 12-16, 22-32, and 38-45, which covered the two helicase ...[more]

PMID: 23887765

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Project description:ImportanceSNRNP200 is a recently identified genetic cause of autosomal dominant retinitis pigmentosa (RP). However, the associated retinal phenotype is not well characterized.ObjectiveTo describe the retinal phenotype in patients with RP secondary to variants in SNRNP200.Design, setting, and participantsThis retrospective, case-series study was performed at 2 tertiary referral centers for inherited retinal diseases. Participants included 9 consecutive patients from 8 families with RP attributed to variants in SNRNP200. Data were collected from August 2017 to March 2018 and analyzed from May to July 2018.Main outcomes and measuresResults of clinical evaluation, multimodal retinal imaging, and molecular genetic testing using targeted next-generation sequencing.ResultsOf the 9 patients included in the analysis (4 female and 5 male; mean [SD] age at presentation, 19 [15] years), each presented with nyctalopia, typically in the first 2 decades of life, although 2 patients experienced symptom onset in middle age. None had any consistent systemic features suggestive of syndromic RP. Retinal imaging studies and electroretinography findings were typical of a rod-predominant dystrophy with later involvement of cone photoreceptors. Phenotypic heterogeneity was typified by 4 unrelated patients with the common c.2041C>T SNRNP200 variant who demonstrated a variable age of disease onset (middle teenage years to the fourth decade of life). Disease progression was slow, with all but 1 patient maintaining visual acuity of better than 20/40 in the better-seeing eye in the fifth and sixth decades of life.Conclusions and relevanceThese data suggest that variants in SNRNP200 result in nonsyndromic RP with a typical phenotype of a rod-predominant dystrophy. Significant phenotypic heterogeneity and nonpenetrance were noted within some affected families. Symptom onset was typically within the first 2 decades of life, with slow progression and well-preserved visual acuities into the fifth and sixth decades.

Project description:ImportanceX-linked retinitis pigmentosa (XLRP) is a severe cause of early-onset RP in male individuals, characterized by degeneration of photoreceptors, an extinguished electroretinogram, and vision loss.ObjectiveTo assess the duration of improvements in retinal sensitivity associated with a single, subretinal injection of cotoretigene toliparvovec (BIIB112/AAV8-RPGR) gene therapy after vitrectomy surgery in the dosed eye over 12 months in part 1 of the Clinical Trial of Retinal Gene Therapy for X-linked Retinitis Pigmentosa Using BIIB112 (XIRIUS) study, compared with untreated fellow eyes and eyes from the untreated subgroup from the Natural History of the Progression of X-Linked Retinitis Pigmentosa (XOLARIS) study.Design, setting, and participantsThis was a post hoc analysis of the XIRIUS and XOLARIS studies. Part 1 of the XIRIUS study was a phase 1, dose-escalation study of 18 male participants 18 years or older enrolled between March 8, 2017, and October 16, 2018, with genetically confirmed RPGR-variant XLRP with active disease and best-corrected visual acuity better than or equal to light perception (cohort 1), 34 to 73 letters (20/40 to 20/200 Snellen equivalent; cohorts 2-3), or greater than or equal to 34 letters (better than or equal to 20/200 Snellen equivalent; cohorts 4-6). Participants from the noninterventional, multicenter, global, prospective XOLARIS clinical study who met the inclusion and exclusion criteria of part 1 of XIRIUS were included as a comparator group (n = 103). Safety assessments included all XIRIUS participants; post hoc associations of retinal sensitivity assessments in XIRIUS only included the 12 participants receiving the 4 highest doses of cotoretigene toliparvovec. Data were analyzed on June 30, 2021.Main outcomes and measuresIncidence of dose-limiting toxicities (DLTs), treatment-emergent adverse events, changes from baseline in retinal sensitivity (as assessed by macular integrity assessment microperimetry), retinal sensitivity response (achievement of ≥7-dB improvement from baseline at ≥5 of 16 central loci), and low-luminance visual acuity were assessed over 24 months.ResultsA total of 18 participants (mean [SD] age, 31.9 [9.4] years; male, 100%) were enrolled and completed the XIRIUS study. A subgroup of 103 participants (mean [SD] age, 30.8 [11.4] years; male, 100%) from the XOLARIS study was included. Administration of the 4 highest doses of cotoretigene toliparvovec (n = 12) among the 18 XIRIUS participants was associated with early improvements in retinal sensitivity. One of 103 untreated participants (1%) in the XOLARIS subgroup achieved improved retinal sensitivity at month 12. No DLTs were noted at any dose, and serious adverse events of reduced visual acuity (n = 2) and noninfective retinitis (n = 1) occurred.Conclusions and relevanceResults suggest that early and sustained improvements in retinal sensitivity and low-luminance visual acuity in some participants through 12 months support consideration of additional clinical trials.Trial registrationClinicalTrials.gov Identifier: XIRIUS: NCT03116113; XOLARIS: NCT04926129.

Dataset Information

Contribution of SNRNP200 sequence variations to retinitis pigmentosa.

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Contribution of SNRNP200 sequence variations to retinitis pigmentosa.

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