Abstract
Inherited retinal dystrophy (IRD) is a heterogenous blinding eye disease and affects more than 200,000 Americans and millions worldwide. By far, 270 protein-coding genes have been identified to cause IRD when defective. However, only one microRNA (miRNA), miR-204, has been reported to be responsible for IRD when a point-mutation occurs in its seed sequence. Previously, we identified that a conserved, polycistronic, paralogous miRNA cluster, the miR-183/96/182 cluster, is highly specifically expressed in all photoreceptors and other sensory organs; inactivation of this cluster in mice resulted in syndromic IRD with multi-sensory defects. We hypothesized that mutations in the miR-183/96/182 cluster in human cause IRD. To test this hypothesis, we perform mutation screening in the pre-miR-183, -96, -182 in >1000 peripheral blood DNA samples of patients with various forms of IRD. We identified six sequence variants, three in pre-miR-182 and three in pre-miR-96. These variants are in the pre-miRNA-182 or -96, but not in the mature miRNAs, and are unlikely to be the cause of the IRD in these patients. In spite of this, the nature and location of these sequence variants in the pre-miRNAs suggest that some may have impact on the biogenesis and maturation of miR-182 or miR-96 and potential roles in the susceptibility to diseases. Although reporting on negative results so far, our study established a system for mutation screening in the miR-183/96/182 cluster in human for a continued effort to unravel and provides deeper insight into the potential roles of miR-183/96/182 cluster in human diseases.
Highlights
Inherited retinal dystrophy (IRD) is a heterogeneous blinding eye disease and affects more than 200,000 Americans and millions worldwide (Daiger et al, 2013)
Pre-miR-182 nt106 G > A This variant was found in 32 IRD patients, including two in CSNB patients, nine cone-rod dystrophy (CRD), one Usher syndrome, four PD and AOFD, three Stargardt disease patients, and 13 patients with Retinitis Pigmentosa (RP) (Table 2 and Figures 2A,B)
In the CSNB group, the rare pre-miR-182 nt105 T appears to be significantly enriched in CSNB patients when compared to the general population data compiled at dbSNP; we only have a small number of CSNB patients in this cohort; whether this “enrichment” is of biological significance or a random bias because of the small number of samples needs to be further investigated in future studies with more CSNB patient samples
Summary
Inherited retinal dystrophy (IRD) is a heterogeneous blinding eye disease and affects more than 200,000 Americans and millions worldwide (Daiger et al, 2013). Based on miRBase Release 22.1 (October, 2018), at least 2654 mature miRNAs (1917 precursors) have been identified in humans In spite of their importance in geneexpression regulation, by far, only one miRNA, miR-204, been identified to cause syndromic IRD with ocular coloboma when a dominant point mutation nt C > T in the seed sequence of miR-204 occurred in a large 5-generation family (Conte et al, 2015). No mutations in other miRNAs have been identified to cause IRD in human, increasing evidences suggest that miRNAs are required for the normal development and functions of photoreceptors and the retina as a whole (Sanuki et al, 2011; Lumayag et al, 2013; Busskamp et al, 2014; Sundermeier et al, 2014; Aldunate et al, 2019)
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