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Micrornas and Inherited Retinal Dystrophies

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Micrornas and Inherited Retinal Dystrophies COMMENTARY COMMENTARY microRNAs and inherited retinal dystrophies Shunbin Xu1 Department of Ophthalmology/Kresge Eye Institute and Department of Anatomy & Cell Biology, School of Medicine, Wayne State University, Detroit, MI 48201 Inherited retinal dystrophies (IRD) are a humans, and the third miRNA in which mu- heterogeneous group of blinding diseases tations cause Mendelian inherited disorders in that affect more than 200,000 Americans humans, after miR-96, which causes nonsyn- and millions worldwide (1). Identification of dromic hearing loss (9, 10), and miR-184 (5, genes that are responsible for IRD when de- 6). Conte et al’s report (8) provides a new fective is of great importance to the basic molecular mechanism of IRD and under- understanding as well as development of ef- scores the importance of miRNA in IRD. ficient gene diagnosis and treatment. Thus miR-204 resides in intron 8 of the tran- Fig. 1. n.37C > T mutation in miR-204 significantly far, 272 genetic loci are linked to various sient receptor potential (TRP) channel gene, changed its predicted target genes. Venn diagram sum- TRPM3 marizing the number of overlapping and unique pre- forms of IRD; among these, 232 protein-cod- , on human chromosome (chr) dicted target genes of wt-miR-204 and mut-miR-204. ing genes have been identified to cause 9q21.12. Through a classic parametric linkage IRD when defective (RetNet, https://sph.uth. analysis, Conte et al. zoomed in on four re- edu/Retnet, last updated April 29, 2015). gions segregating with the phenotypes, in- medaka fish suggested its important roles in microRNAs (miRNAs) are endogenous, cluding 9q21 (8). Through exon sequencing, the development and function of the retina small, noncoding, regulatory RNAs (2). extensive bioinformatic studies to eliminate (13, 14), lens (13–15), and RPE (12). Knock- Since their discovery in 1993 (3, 4), miRNAs nondisease-causing variants using multiple downofmiR-204infishresultedinmicro- have proven to play important roles in publically available databases, including the phthalmia, abnormal lens formation, altered the fine-tuning of gene expression at post- Exon Variant Server of the National Heart, dorso-ventral (D-V) patterning of the retina, transcriptional levels (2). In spite of their Lung and Blood Institute Exome Sequencing and coloboma (13). importance in gene-expression regulation, Project, dbSNP, and the 1000 genomes proj- MutationsinmiRNAseitherdisrupttheir few mutations of individual miRNAs have ect, and segregation studies, Conte et al. biogenesis and, therefore, expression levels of been found to cause Mendelian inherited dis- found that a point mutation in miR-204, the mature miRNAs, and/or change their eases in humans, raising doubts about their n.37C > T, cosegregates with the disease downstream target genes (5, 6, 9, 10). The importance in normal development and func- but is not present in all control databases seed sequence of a miRNA is the major de- tions, and whether mutations in a miRNA and 21 sporadic cases of retinal dystrophy terminant of its downstream target genes can have significant functional impact to with microphthalmia anophthalmia and and, therefore, functions of the miRNA cause Mendelian inherited diseases, including coloboma (MAC), 457 patients with isolated (16). The mutation identified in this fam- IRD.Recently,apointmutationintheseed MAC, and 672 patients with autosomal dom- ily, n.37C > T, is located at the fourth residue > sequence of miR-184 was reported to cause inant IRD, suggesting that n.37C Tisthe of the seed sequence of miR-204. Conte et al. familial keratoconus with cataract (5) and an disease-causing mutation in this family (8). demonstrated that this mutation has no sig- anterior-segment dysplasia syndrome with Publically available control databases have nificant impact on the secondary structure of e ndothelial dystrophy, iris hypoplasia, con- become invaluable sources for evaluating pre-miR-204 and biogenesis of miR-204 (8). genital cataract, and stromal thinning (6), the nature of a mutation and excluding However, target prediction analysis revealed suggesting that miR-184 is required for nondisease-causing genomic variants. The a loss of 442 predicted targets of wild-type anterior-segment development and function, Conte et al. report exemplifies an effective miR-204 (wt-miR-204) and a gain of 994 and proving that mutations in an individual approach for identification of disease-caus- new predicted target genes of the mutant miRNA can cause inherited ocular disease in ing mutations in a postgenomic era. miR-204 (mut-miR-204) (Fig. 1) (8), in humans. In mice, Lumayag et al. demon- In the family studied by Conte et al. (8), all which genes involved in eye development, strated that inactivation of the miR-183/96/ affected individuals had progressive retinal synaptic function, cell adhesion, axon guid- 182 cluster gene causes syndromic IRD with dystrophy, vision loss, and coloboma; multi- ance, D-V axis formation, and cellular re- multisensory defects (7), suggesting that de- ple affected individuals underwent bilateral sponse to stress are significantly enriched. fects in miRNA genes can cause IRD in mam- cataract surgery at early ages, suggesting lens Through overexpression of wt-miR-204 mals. However, until now, no mutations in defects; and the proband also showed irido- and mut-miR-204 in a human RPE cell line miRNAs have been found to cause IRD in lenticular adhesions and scattered retinal pig- and gene-expression profiling, Conte et al. humans. In PNAS, Conte et al. report a dom- mented epithelia (RPE) mottling. Mutation showed that n.37C > Tmutationresultedin inant mutation in miR-204 that causes IRD inmiR-204asthecauseofthediseaseis associated with ocular coloboma in a large consistent with the observation that miR- five-generation family (8). This paper is the 204 is preferentially expressed in multiple Author contributions: S.X. wrote the paper. firstreporttoshowthatapointmutationin ocular tissues, including the retina, RPE, The author declares no conflict of interest. an individual miRNA results in significant ciliary body, and lens (11–13). In addition, See companion article on page E3236 in issue 25 of volume 112. functional consequence and causes IRD in previous in vitro and in vivo studies in 1Email: [email protected]. www.pnas.org/cgi/doi/10.1073/pnas.1511019112 PNAS | July 21, 2015 | vol. 112 | no. 29 | 8805–8806 Downloaded by guest on September 27, 2021 significant changes in expression of target different mutations in the same protein-cod- miRNAs are generally considered as fine- genes of miR-204. Furthermore, overexpres- ing gene can cause different forms of IRD (1). tuners of gene expression, providing quanti- sion of the mut-miR-204 in fish resulted in The paucity of Mendelian inherited dis- tative modulation of their downstream genes phenotypes similar to the ones observed in eases caused by miRNA mutations is attrib- (2). Mature miRNAs function by base-pairing the affected individuals in the family, includ- uted, in part, to their small sizes (8). However, with target sites in the 3′UTRs of the tran- ing microphthalmia, coloboma, retinal degen- scripts of their downstream target genes in- eration, and vision loss. The resemblance to Conte et al. report a ducing breakdown and/or translation inhi- fish with mut-miR-204 overexpression is dominant mutation in bition of the transcripts. Mutations in target more than to fish with either overexpression sites of downstream genes could interrupt the (8) or knockdown of wt-miR-204 (13), sug- miR-204 that causes IRD miRNA regulatory network and cause or con- gesting that gain-of-function of mut-miR-204 associated with ocular tribute to disease (18, 19). Therefore, muta- is the major mechanism underlying the de- coloboma in a large five- ′ fects observed in the affected individuals of tion screening in the 3 UTRs of protein- the family, although loss-of-function also generation family. coding genes that are known to cause IRD when defective and that carry target sites may contribute to the disease. This conclusion disease-causing mutations in miRNAs may for miR-204 and other retina-enriched is further supported by the fact that deletion have been significantly underestimated, as TRPM3 miRNAs is warranted in searching for new encompassing the gene have not been miRNAs are one of noncoding elements of reported to cause ocular diseases (8). Thus, the genome and have been largely neglected disease-causing mutations. More broadly, this is the first example of a miRNA mutation in mutation screenings in the past. With the genetic variants in miRNAs and their target causing an inherited disease in human with principle proven by the Conte et al. report sites in protein-coding genes may quantita- gain-of-function as the main mechanism. (8), it is reasonable to propose that mutations tively modulate disease-related genetic net- Intriguingly, Conte et al. (8) demonstrated in other miRNAs that are enriched in the works and contribute to the pathogenesis of that overexpression and knockdown of wt- retina and other ocular tissues could also multifactorial ocular diseases, including age- miR-204 and overexpression of mut-miR- cause various forms of IRD and other related macular degeneration, glaucoma, and 204 in fish resulted in overlapping but differ- inherited ocular disorders in humans (17). diabetic retinopathy. ent phenotypes. This complexity reflects a characteristic nature of miRNA function—one miRNA can have different functions in differ- 1 Daiger SP, Sullivan LS, Bowne SJ (2013) Genes and mutations family by altering pre-miRNA processing. Hum Mol Genet ent tissues at different development stages. causing retinitis pigmentosa. Clin Genet 84(2):132–141. 21(3):577–585. 2 Bartel DP (2004) MicroRNAs: Genomics, biogenesis, mechanism, 11 Deo M, Yu JY, Chung KH, Tippens M, Turner DL (2006) Detection Further studies are needed to unravel detailed and function. Cell 116(2):281–297. of mammalian microRNA expression by in situ hybridization with RNA mechanisms of the different effects of the wt- 3 Lee RC, Feinbaum RL, Ambros V (1993) The C.
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