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Missense Variants in the Conserved Transmembrane M2 Protein Domain of KCNJ13 Associated With Retinovascular Changes in Humans and Zebrafish

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Missense Variants in the Conserved Transmembrane M2 Protein Domain of KCNJ13 Associated With Retinovascular Changes in Humans and Zebrafish

Maria Toms et al. Exp Eye Res.

Abstract

Mutations in KCNJ13 are associated with two retinal disorders; Leber congenital amaurosis (LCA) and snowflake vitreoretinal degeneration (SVD). We describe a novel fibrovascular proliferation in the retina of two affected members of a KCNJ13-related LCA family with a homozygous c.458C > T, p.(Thr153Ile) missense mutation. Optical coherence tomography retinal imaging of the kcnj13 mutant zebrafish (obelixtd15 c.502T > C, p.[Phe168Leu]) revealed a late onset retinal degeneration at 12 months, with retinal thinning and associated retinovascular changes, including increased vessel calibre and vitreous deposits. Both human and zebrafish variants are missense and located within the conserved transmembrane M2 protein domain, suggesting that disruption of this region may contribute to retinovascular changes as an additional feature to the previously described LCA phenotype. Close monitoring of other patients with similar mutations may be required to minimise the ensuing retinal damage.

Conflict of interest statement

None.

Figures

Fig. 1
Fig. 1
Location of reported KCNJ13 mutations on the Kir7.1 protein. (a) Schematic of the linear structure of Kir7.1 shows two transmembrane α helices (M1 and M2) with cytoplasmic NH2 and COOH termini, separated by an extracellular pore-forming loop that acts as a selectivity filter (H5). The location of published mutations is indicated and color-coded according to their associated disease. The missense mutation (p.Thr153Ile [T153I]) identified in families A and B in this study is highlighted with *. (b) Human Kir7.1 monomer model generated using Phyre2; the crystal structure of Kir3.2 was used as a template. The T153I mutation is highlighted in red. (c) Alignment of the human, mouse and zebrafish Kir7.1 protein sequences demonstrates the close proximity of the obelixtd15 (obetd15) zebrafish missense change (p.Phe168Leu) to the patient T153I mutation within the fully conserved M2 domain. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)
Fig. 2
Fig. 2
Early clinical features of the KCNJ13 retinopathy. Ultra-wide field fundus imaging with Optos (Dunfermline, Scotland) of the right and left eye from patient A-2 with a missense mutation (p.Thr153Ile) in KCNJ13 at age 9 (a, b) and at age 15 (c, d). It shows early stage retinal vessel attenuation and progressive retinal pigmentation in a nummular pattern. At age 15, signs of preretinal fibrosis can be seen over the optic disc extending across the arcade. OCT of the left eye at age 9 (e), prior to the onset of vitreous haemorrhage, reveals the presence of retinal lamination but with foveal hypoplasia; this was also seen in patient A-1.
Fig. 3
Fig. 3
Retinal vasculature in KCNJ13 patients. Ultra-wide field fluorescein angiography (FFA) using Optos (Dunfermline, Scotland) of the right eye from two unrelated patients with a missense mutation (p.Thr153Ile) in KCNJ13 compared to normal control male age 32 years (a–c). Panel Patient A-1, 20 years old, (d) color fundus images showing vasoproliferative response around the arcades, widespread pan-retinal photocoagulation scars overlying the pigmentary retinopathy; (e) shows leakage (first seen in arterial phase, data not shown) in the venous phase with extensive leakage in the late phase (f). Panel Patient B-2, 10 years old, (g) color fundus images showing patchy areas of nummular pigmentary retinopathy; (h) FFA shows hyperfluorescence in areas of retinopathy with an area of hypofluorescence at the macula which coincides with delineated area of chorioretinal atrophy (choroidal vessels can be seen), but no evidence of leakage at any phase (i).
Fig. 4
Fig. 4
Retinal vasculature in obetd15 zebrafish. OCT en face images of the dorsal retina show inner retinal vessels emerging from the optic nerve region in the wild-type (a) and obetd15 (b) fish at 12 months post-fertilization, displaying abnormal blood vessel appearance in the mutant retina. Cross-sectional B-scans from wild-type (c) and obetd15 (d) fish also demonstrate notable differences in vessel size (vessels indicated with *). Numbered brackets (1–4) on the cross-sections represent areas analyzed in the corresponding en face images. Fibrous material was apparent at each depth examined in the vitreous of the obetd15 retina (3, 4) but was not seen on the wild-type images (1, 2). Hyper-reflective deposits were also noted in the vitreous of the obetd15 retina on both B-scan (e) and en face (f) images, indicated with arrows. Graph (g) shows retinal vessel thickness plotted against distance from the optic nerve in wild-type and obetd15 zebrafish. Scale bars = 50 μm.

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