Missense variants in the conserved transmembrane M2 protein domain of KCNJ13 associated with retinovascular changes in humans and zebrafish

Maria Toms,Adam M Dubis,Wei Sing Lim,Andrew R Webster,Michael B Gorin,Mariya Moosajee

doi:10.1016/j.exer.2019.107852

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.

Highlights

The KCNJ13 gene encodes Kir7.1, a member of the inwardly-rectifying potassium channel family (Krapivinsky et al, 1998; Partiseti et al, 1998; Doring et al, 1998)
We have described here retinovascular abnormalities in two siblings (A-1 and A-2) with homozygous c.458C > T, p.(Thr153Ile) KCNJ13 mutations
Early and late leakage of retinal vessels with neovascularization and vitreous haemorrhage was observed, which have not been noted in KCNJ13-Leber congenital amaurosis (LCA) previously (Sergouniotis et al, 2011; Pattnaik et al, 2015; Perez-Roustit et al, 2017)

Summary

Introduction

The KCNJ13 gene (potassium voltage-gated channel subfamily J member 13) encodes Kir7.1, a member of the inwardly-rectifying potassium channel family (Krapivinsky et al, 1998; Partiseti et al, 1998; Doring et al, 1998). LCA is a severe early onset retinal dystrophy with RPE and photoreceptor loss causing blindness from birth (Kumaran et al, 2017). It is characterized by sensory nystagmus, amaurotic pupils and absent electrical signals on an electroretinogram. Retinal features including macular atrophy, pigment deposits and vessel attenuation have been reported in LCA patients with KCNJ13 mutations (Sergouniotis et al, 2011; Pattnaik et al, 2015; Perez-Roustit et al, 2017). The visual acuity is normal and retinal function testing reveals only mild abnormalities

Methods

Results

Conclusion