Kandaswamy, S., Zobel, L., John, B. et al. | Cell Death Discovery | Vol 8, Article 387 | 2022 | doi.org/10.1038/s41420-022-01185-0
Abstract
Retinitis pigmentosa is a group of progressive inherited retinal dystrophies that may present clinically as part of a syndromic entity or as an isolated (nonsyndromic) manifestation. In an Indian family suffering from retinitis pigmentosa, we identified a missense variation in CNGA1 affecting the cyclic nucleotide binding domain (CNBD) and characterized a mouse model developed with mutated CNBD. A gene panel analysis comprising 105 known RP genes was used to analyze a family with autosomal-recessive retinitis pigmentosa (arRP) and revealed that CNGA1 was affected. From sperm samples of ENU mutagenesis derived F1 mice, we re-derived a mutant with a Cnga1 mutation. Homozygous mutant mice, developing retinal degeneration, were examined for morphological and functional consequences of the mutation. In the family, we identified a rare CNGA1 variant (NM_001379270.1) c.1525 G > A; (p.Gly509Arg), which co-segregated among the affected family members. Homozygous Cnga1 mice harboring a (ENSMUST00000087213.12) c.1526 A > G (p.Tyr509Cys) mutation showed progressive degeneration in the retinal photoreceptors from 8 weeks on. This study supports a role for CNGA1 as a disease gene for arRP and provides new insights on the pathobiology of cGMP-binding domain mutations in CNGA1-RP.
Introduction
Retinitis pigmentosa (RP) is a group of Inherited Retinal Degeneration/Dystrophies (IRD), with a global prevalence of 1 in 3000–7000 [1]. RP is characterized by abnormalities in the photoreceptors (rods and cones) or the retinal pigment epithelium (RPE) with all types of inheritance patterns documented. RP can occur either as isolated or as syndrome with the involvement of other organs such as the associated hearing loss in USHER syndrome. About 90 genes are known until date to cause RP (Retnet database http://www.sph.uth.tmc.edu/retnet/). Most of the gene variants in RP are directly associated with the phototransduction cascade, such as RHO (rhodopsin), which are known to cause 25–30% of adRP. Phototransduction begins with the detection of light photons by rhodopsin, and this triggers several signaling steps that eventually convert the light signal into an electrical signal being transmitted to the brain. Key steps of this downstream signaling are mediated by proteins encoded by genes linked to RP. This list includes genes encoding for the subunits of rod phosphodiesterase (PDE6A and PDE6B) and rod cyclic nucleotide gated (CNG) channel (CNGA1 and CNGB1). CNGA1 encodes the A (or alpha) subunit of the rod CNG channel, which is a heterotetrameric channel complex formed by three CNGA1 and one CNGB1 subunits; its structure has been recently solved [2]. The rod CNG channel along with CNGB1 forms a cyclic guanosine monophosphate (cGMP)-gated cation channel found in the rod photoreceptor outer segment plasma membrane [3]. Each CNG channel subunit consist of six transmembrane domains, and both, the N-terminal and the C-terminal domain, are in the cytoplasm [2]. While the A subunit is essential for the principle formation of a functional cGMP-gated channel, the B subunit is important for transport of the channel to the plasma membrane of the rod outer segment and confers specific properties to the channel complex such as rapid on-off kinetics and sensitivity to the pharmacological inhibitor L-cis-diltiazem [4, 5].
In the present study we report a rare variant (c.1525 G > A; p.Gly509Arg) of the CNGA1 gene in a family suffering from arRP. Animal models for retinal degeneration usually provide insights into pathological mechanism of disease progression and assist in designing therapeutic strategies. We re-derived a Cnga1 (c1526A > G; pTyr509Cys) mouse mutant from the ENU archive [6]. This mutation falls within the same protein domain as the one observed in the human family. We report herein the retinal degeneration by a longitudinal morphological and physiological analysis.
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