Dataset Information

A novel KCNV2 mutation in a patient taking hydroxychloroquine associated with cone dystrophy with supernormal rod response.

ABSTRACT:

Background

Cone dystrophy with supernormal rod response (CDSRR) is a rare inherited retinal degeneration. A patient superimposed with medical conditions requiring use of hydroxychloroquine (HCQ) may obscure accurate diagnosis of CDSRR. Herein, we report a referral case for HCQ retinopathy screening. Comprehensive ophthalmic examinations, however, guided the diagnosis of CDSRR from a novel mutation in potassium voltage-gated channel modifier subfamily V member 2 (KCNV2) gene.

Materials and methods

Comprehensive ophthalmic examinations were evaluated for two patients whose parents are first cousins. Direct sanger sequencing of KCNV2 was applied to confirm the mutation.

Results

A 38-year-old male proband was referred for HCQ retinopathy screening after taking HCQ for systemic lupus erythematosus (SLE). Fundus examination showed bull's eye pattern, and photoreceptor loss in the foveal region of both eyes was noted on spectral domain-optical coherence tomography (SD-OCT). The full-field electroretinography (ffERG) revealed a disproportionate increase in scotopic maximal response with implicit time delay, as well as universal cone dysfunction. Proband's 24-year-old sister had similar ffERG pattern in both eyes. Direct sanger sequencing of KCNV2 gene revealed a novel homozygous mutation c.280_281 insG (p.Ala94GlyfsTer278), confirming a diagnosis of CDSRR.

Conclusions

We report a novel KCNV2 mutation in a consanguineous family. The unique ffERG features of CDSRR are pathognomonic and thus crucial in guiding clinicians toward genetic testing of the KCNV2 gene. Altogether, multimodal imaging, ffERG, and detailed history taking are important diagnostic tools for differentiating between acquired and inherited retinal disorders.

SUBMITTER: Liu PK

PROVIDER: S-EPMC10234695 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Publications

A novel KCNV2 mutation in a patient taking hydroxychloroquine associated with cone dystrophy with supernormal rod response.

Liu Pei-Kang PK Ryu Joseph J Yeh Lung-Kun LK Chen Kuan-Jen KJ Tsang Stephen H SH Liu Laura L Wang Nan-Kai NK

Ophthalmic genetics 20210507 4

<h4>Background</h4>Cone dystrophy with supernormal rod response (CDSRR) is a rare inherited retinal degeneration. A patient superimposed with medical conditions requiring use of hydroxychloroquine (HCQ) may obscure accurate diagnosis of CDSRR. Herein, we report a referral case for HCQ retinopathy screening. Comprehensive ophthalmic examinations, however, guided the diagnosis of CDSRR from a novel mutation in potassium voltage-gated channel modifier subfamily V member 2 (<i>KCNV2</i>) gene.<h4>Ma ...[more]

PMID: 33960280

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Project description:UnlabelledMutations in RPGRIP1 are associated with early onset retinal degenerations in humans and dogs. Dogs homozygous for a 44 bp insertion including a polyA(29) tract potentially leading to premature truncation of the protein, show cone rod degeneration. This is rapid and blinding in a colony of dogs in which the mutation was characterised but in dogs with the same mutation in the pet population there is very variable disease severity and rate of progression.ObjectiveWe hypothesized that this variability must be associated with leakiness of the RPGRIP1 mutation, allowing continued RPGRIP1 production. The study was designed to discover mechanisms that might allow such leakiness.MethodsWe analysed alternate start sites and splicing of RPGRIP1 transcripts; variability of polyA(n) length in the insertion and slippage at polyA(n) during transcription/translation.Results and significanceWe observed a low rate of use of alternative start codons having potential to allow forms of transcript not including the insertion, with the possibility of encoding truncated functional RPGRIP1 protein isoforms. Complex alternative splicing was observed, but did not increase this potential. Variable polyA(n) length was confirmed in DNA from different RPGRIP1(-/-) dogs, yet polyA(n) variability did not correspond with the clinical phenotypes and no individual was found that carried a polyA(n) tract capable of encoding an in-frame variant. Remarkably though, in luciferase reporter gene assays, out-of-frame inserts still allowed downstream reporter gene expression at some 40% of the efficiency of in-frame controls. This indicates a major role of transcriptional or translational frameshifting in RPGRIP1 expression. The known slippage of reverse transcriptases as well as RNA polymerases and thermostable DNA polymerases on oligoA homopolymers meant that we could not distinguish whether the majority of slippage was transcriptional or translational. This leakiness at the mutation site may allow escape from severe effects of the mutation for some dogs.

Dataset Information

A novel KCNV2 mutation in a patient taking hydroxychloroquine associated with cone dystrophy with supernormal rod response.

Background

Materials and methods

Results

Conclusions

Publications

A novel KCNV2 mutation in a patient taking hydroxychloroquine associated with cone dystrophy with supernormal rod response.

Similar Datasets

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