Retinitis pigmentosa and bilateral cystoid macular oedema in a patient heterozygous for the <i>RIM1</i> mutation previously associated with cone-rod dystrophy 7

Warwick, Alasdair; Shawkat, Fatima; Lotery, Andrew

doi:10.1080/13816810.2016.1183215

Cited by 7 publications

(7 citation statements)

References 15 publications

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“…46 Interestingly, a RIMS1 variant was found to co-segregate with autosomal-dominant cone-rod dystrophy (CORD7 [MIM: 603649]) in a British family, implicating a gene with a synaptic function in an IRD. [47][48][49] In a mouse model carrying the same Rims1 variant as the human CORD7 (p.Arg655His), the mutant was shown to modify Rims1 function in regulating voltage dependent Ca 2þ channel currents. 50 A Rims1 variant on different presynaptic voltagedependent calcium channels (VDCCs) might eventually lead to CORD and enhanced cognitive abilities.…”

Section: Discussionmentioning

confidence: 99%

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

Mechaussier

Almoallem

Zeitz

et al. 2020

The American Journal of Human Genetics

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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.

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Section: Discussionmentioning

confidence: 99%

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

Mechaussier

Almoallem

Zeitz

et al. 2020

The American Journal of Human Genetics

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“…RIM3␥ and RIM4␥ are also present in retinal ribbon synapses (9). Interestingly, a point mutation in the C 2 A domain of RIM1 is associated with a cone-roddystrophy (CORD7) and dysfunction of vision (179,259,263,432). This defect could result from defective retinal transmission from inner retinal neurons, e.g., bipolar cells, but photoreceptors are also affected.…”

Section: Rim Proteins and Rim-binding Proteinsmentioning

confidence: 99%

Sensory Processing at Ribbon Synapses in the Retina and the Cochlea

Moser

Grabner

Schmitz

2020

Physiological Reviews

161

214

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In recent years, sensory neuroscientists have made major efforts to dissect the structure and function of ribbon synapses which process sensory information in the eye and ear. This review aims to summarize our current understanding of two key aspects of ribbon synapses: 1) their mechanisms of exocytosis and endocytosis and 2) their molecular anatomy and physiology. Our comparison of ribbon synapses in the cochlea and the retina reveals convergent signaling mechanisms, as well as divergent strategies in different sensory systems.

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“…The first implication of RIMS1 in retinal disease came from a report of a single large family 21 22. A later report described a patient with the same RIMS1 variant, but a different phenotype (retinitis pigmentosa),23 and there have further variants reported, but without detailed evidence to secure a causative relationship 24–26. Implication of AHR in retinal disease comes from a report of a single family 27.…”

Section: Discussionmentioning

confidence: 99%

Exploring the mutational landscape of genes associated with inherited retinal disease using large genomic datasets: identifying loss of function intolerance and outlying propensities for missense changes

et al. 2022

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BackgroundLarge databases permit quantitative description of genes in terms of intolerance to loss of function (‘haploinsufficiency’) and prevalence of missense variants. We explored these parameters in inherited retinal disease (IRD) genes.MethodsIRD genes (from the ‘RetNet’ resource) were classified by probability of loss of function intolerance (pLI) using online Genome Aggregation Database (gnomAD) and DatabasE of genomiC varIation and Phenotype in Humans using Ensembl Resources (DECIPHER) databases. Genes were identified having pLI ≥0.9 together with one or both of the following: upper bound of CI <0.35 for observed to expected (o/e) ratio of loss of function variants in the gnomAD resource; haploinsufficiency score <10 in the DECIPHER resource. IRD genes in which missense variants appeared under-represented or over-represented (Z score for o/e ratio of <−2.99 or >2.99, respectively) were also identified. The genes were evaluated in the gene ontology Protein Analysis THrough Evolutionary Relationships (PANTHER) resource.ResultsOf 280 analysed genes, 39 (13.9%) were predicted loss of function intolerant. A greater proportion of X-linked than autosomal IRD genes fulfilled these criteria, as expected. Most autosomal genes were associated with dominant disease. PANTHER analysis showed >100 fold enrichment of spliceosome tri-snRNP complex assembly. Most encoded proteins were longer than the median length in the UniProt database. Fourteen genes (11 of which were in the ‘haploinsufficient’ group) showed under-representation of missense variants. Six genes (SAMD11, ALMS1, WFS1, RP1L1, KCNV2, ADAMTS18) showed over-representation of missense variants.ConclusionA minority of IRD-associated genes appear to be ‘haploinsufficient’. Over-representation of spliceosome pathways was observed. When interpreting genetic tests, variants found in genes with over-representation of missense variants should be interpreted with caution.

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Retinitis pigmentosa and bilateral cystoid macular oedema in a patient heterozygous for the RIM1 mutation previously associated with cone-rod dystrophy 7

Cited by 7 publications

References 15 publications

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

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

Sensory Processing at Ribbon Synapses in the Retina and the Cochlea

Exploring the mutational landscape of genes associated with inherited retinal disease using large genomic datasets: identifying loss of function intolerance and outlying propensities for missense changes

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