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A novel p.Gly603Arg mutation in CACNA1F causes Aland island eye disease and incomplete congenital stationary night blindness phenotypes in a family.

ABSTRACT: PURPOSE: To report, for the first time, that X-linked incomplete congenital stationary night blindness (CSNB2A) and Åland island eye disease (AIED) phenotypes coexist in a molecularly confirmed pedigree and to present novel phenotypic characteristics of calcium channel alpha-1F subunit gene (CACNA1F)-related disease. METHODS: Two affected subjects (the proband and his maternal grandfather) and an unaffected obligate carrier (the proband's mother) underwent detailed ophthalmological evaluation, fundus autofluorescence imaging, and spectral-domain optical coherence tomography. Goldmann visual field assessment and full-field electroretinogram (ERG) were performed in the two affected subjects, and multichannel flash visual evoked potential was performed on the proband. Scotopic 15 Hz flicker ERG series were performed in both affected subjects to evaluate the function of the slow and fast rod pathways. Haplotype analysis using polymorphic microsatellite markers flanking CACNA1F was performed in all three family members. The proband's DNA was sequenced for mutations in the coding sequence of CACNA1F and nyctalopin (NYX) genes. Segregation analysis was performed in the family. RESULTS: Both affected subjects had symptoms of nonprogressive nyctalopia since childhood, while the proband also had photophobia. Both cases had a distance visual acuity of 20/50 or better in each eye, normal contrast sensitivity, and an incomplete type of Schubert-Bornschein ERGs. The proband also had high myopia, a mild red-green color deficit, hypopigmented fundus, and foveal hypoplasia with no evidence of chiasmal misrouting. Spectral-domain optical coherence tomography confirmed the presence of foveal hypoplasia in the proband. The clinical phenotype of the proband and his maternal grandfather fit the clinical description of AIED and CSNB2A, respectively. The fundus autofluorescence and the visual fields were normal in both cases; the scotopic 15 Hz flicker ERG demonstrated only fast rod pathway activity in both. Both affected cases shared the same haplotype across CACNA1F. The proband carried a novel hemizygous c.1807G>C mutation (p.G603R) in the CACNA1F gene. The change segregated with the disease phenotypes and was not identified in 360 control chromosomes. No mutations were identified in NYX. CONCLUSIONS: This report of a missense mutation in CACNA1F causing AIED and CSNB2A phenotypes in a family confirms that both diseases are allelic and that other genetic or environmental modifiers influence the expression of CACNA1F. This is the first report to suggest that in CACNA1F-related disease, the rod system activity is predominantly from the fast rod pathways.

SUBMITTER: Vincent A

PROVIDER: S-EPMC3244487 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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A novel p.Gly603Arg mutation in CACNA1F causes Åland island eye disease and incomplete congenital stationary night blindness phenotypes in a family.

Vincent Ajoy A Wright Tom T Day Megan A MA Westall Carol A CA Héon Elise E

Molecular vision 20111215

<h4>Purpose</h4>To report, for the first time, that X-linked incomplete congenital stationary night blindness (CSNB2A) and Åland island eye disease (AIED) phenotypes coexist in a molecularly confirmed pedigree and to present novel phenotypic characteristics of calcium channel alpha-1F subunit gene (CACNA1F)-related disease.<h4>Methods</h4>Two affected subjects (the proband and his maternal grandfather) and an unaffected obligate carrier (the proband's mother) underwent detailed ophthalmological ...[more]

PMID: 22194652

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Project description:Importance:Congenital stationary night blindness (CSNB) implies a stable condition, with the major symptom being nyctalopia present at birth. Pediatric clinical presentation and the course of different genetic subtypes of CSNB have not, to our knowledge, been well described in the era of molecular genetic diagnosis. Objective:To describe the presentation and longitudinal clinical characteristics of pediatric patients with molecularly confirmed TRPM1-associated complete CSNB (cCSNB). Design, Setting, Participants:This study was conducted at the University of Iowa from January 1, 1990, to July 1, 2015, and was a retrospective, longitudinal case series of 7 children (5 [71.4%] female) with TRPM1-associated cCSNB followed up for a mean (SD) of 11.1 (2.8) years. Main Outcomes and Measures:History, ophthalmologic examination findings, full-field electroretinogram (ffERG) results, full-field stimulus threshold testing results, Goldmann visual field results, optical coherence tomography results, and molecular genetic results were evaluated. Presenting symptoms and signs, the correlation of refractive error with electroretinography, and clinical evolution were analyzed. Results:Seven patients (5 [71.4%] female) presented early in childhood with strabismus (n = 6 [86%]), myopia (n = 5 [71%]), and/or nystagmus (n = 3 [43%]). The mean (SD) age at presentation was 8 (4) months and for receiving a diagnosis by ffERG was 7.3 years, with molecular diagnosis at 9.7 years. The mean (SD) length of follow-up was 11 (2.8) years. The best-corrected visual acuity at the most recent visit averaged 20/30 in the better-seeing eye (range, 20/20-20/60). The mean (SD) initial refraction was -2.80 (4.42) diopters (D) and the mean refraction at the most recent visit was -8.75 (3.53) D (range, -4.00 to -13.75 D), with the greatest rate of myopic shift before age 5 years. Full-field electroretinogram results were electronegative, consistent with cCSNB, without a significant change in amplitude over time. No patient or parent noted night blindness at presentation; however, subjective nyctalopia was eventually reported in 5 of 7 patients (71%). The full-field stimulus threshold testing results were moderately subnormal (-29.7 [3.8] dB; normal -59.8 [4.0] dB). Goldmann visual field results were significant for full I-4e, but constricted I-2e isopter. Eight different mutations or rare variants in TRPM1 predicted to be pathogenic were detected, with 3 novel variants. Conclusions and Relevance:Children with TRPM1-associated cCSNB presented before school age with progressive myopia as well as strabismus and nystagmus (but not nyctalopia), with stable, electronegative ffERG results, mildly subnormal full-field stimulus threshold testing results, and a constricted I2e isopter on perimetry. These findings suggest that ffERG and cCSNB genetic testing should be considered for children who present with early-onset myopia, especially in the presence of strabismus and/or nystagmus, and that TRPM1-associated cCSNB is a channelopathy that may present without complaints of night blindness in childhood.

Dataset Information

A novel p.Gly603Arg mutation in CACNA1F causes Aland island eye disease and incomplete congenital stationary night blindness phenotypes in a family.

Publications

A novel p.Gly603Arg mutation in CACNA1F causes Åland island eye disease and incomplete congenital stationary night blindness phenotypes in a family.

Similar Datasets

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