Loss of Function of RIMS2 Causes a Syndromic Congenital Cone-Rod Synaptic Disease with Neurodevelopmental and Pancreatic Involvement

Abstract

Congenital cone-rod synaptic disorder (CRSD), also known as incomplete congenital stationary night blindness (iCSNB), is a non-progressive inherited retinal disease (IRD) characterized by night blindness, photophobia, and nystagmus, and distinctive electroretinographic features. Here, we report bi-allelic RIMS2 variants in seven CRSD-affected individuals from four unrelated families. Apart from CRSD, neurodevelopmental disease was observed in all affected individuals, and abnormal glucose homeostasis was observed in the eldest affected individual. RIMS2 regulates synaptic membrane exocytosis. Data mining of human adult bulk and single-cell retinal transcriptional datasets revealed predominant expression in rod photoreceptors, and immunostaining demonstrated RIMS2 localization in the human retinal outer plexiform layer, Purkinje cells, and pancreatic islets. Additionally, nonsense variants were shown to result in truncated RIMS2 and decreased insulin secretion in mammalian cells. The identification of a syndromic stationary congenital IRD has a major impact on the differential diagnosis of syndromic congenital IRD, which has previously been exclusively linked with degenerative IRD.

Optic Atrophy and Inner Retinal Thinning in CACNA1F-Related Congenital Stationary Night Blindness

“…Inner retinal thinning was seen in the three subjects for whom OCT was available, and RNFL thinning was shown in two of them [15]. Whilst the authors advise optic disc and inner retinal changes should be interpreted with caution in the context of myopia, it is noted that none of the cases had high myopia (range: +6.00 to −4.50 D; only three were myopic) [15]. In 1983 Heckenlively et al reported optic disc anomalies (interpreted as representing atrophy, dysplasia, or both) in subjects with CSNB; five had tilted discs with a lack of visible temporal disc tissue, two had dysplastic nerves and three had disc pallor without tilt [81].…”

“…To date, a few cases in the literature have documented optic disc pallor or atrophy in CACNA1F-related iCSNB [18][19][20] and these reports are limited to the clinical appearance, rather than the graded measurement of optic disc pallor or ganglion cell structural integrity. All seven reported cases of iCSNB associated with RIMS2, a regulator of synaptic membrane exocytosis localized to rod photoreceptors and the outer plexiform layer, from 3 unrelated, ethnically diverse families demonstrated clinically appreciable optic disc pallor [15]. Inner retinal thinning was seen in the three subjects for whom OCT was available, and RNFL thinning was shown in two of them [15].…”

“…All seven reported cases of iCSNB associated with RIMS2, a regulator of synaptic membrane exocytosis localized to rod photoreceptors and the outer plexiform layer, from 3 unrelated, ethnically diverse families demonstrated clinically appreciable optic disc pallor [15]. Inner retinal thinning was seen in the three subjects for whom OCT was available, and RNFL thinning was shown in two of them [15]. Whilst the authors advise optic disc and inner retinal changes should be interpreted with caution in the context of myopia, it is noted that none of the cases had high myopia (range: +6.00 to −4.50 D; only three were myopic) [15].…”

“…Most recently, ERG findings compatible with iCSNB were also described in patients with biallelic loss-of-function variants in RIMS2. All RIMS2 patients had optic disc pallor with most demonstrating retinal vascular attenuation; affected individuals also displayed neurodevelopmental disease and infrequently abnormal glucose homeostasis, making this a syndromic form of iCSNB [15]. Given the phenotypic variability within iCSNB and the fact that many patients complain of photophobia [10], rather than nyctalopia [1,16], "congenital rod-cone synaptic disorder" is a recently proposed term for the CACNA1F-related disorder [17].…”

Human photoreceptor cells from different macular subregions have distinct transcriptional profiles

“…4 ). The most foveal enriched cone photoreceptor gene was RIMS2 , a regulator of synaptic membrane exocytosis that has been implicated in a congenital cone-rod synaptic disorder ( 18 ). Several additional genes implicated in synaptic transmission were enriched in foveal cone photoreceptors, likely reflecting the unique synaptic characteristics of foveal cones.…”