Alternative splicing and retinal degeneration

Liu, Melissa M.; Zack, Donald J.

doi:10.1111/cge.12181

Cited by 78 publications

(66 citation statements)

References 68 publications

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“…Another such example includes cleavage and polyadenylation factor I subunit 1 (CLP1), a multifunctional kinase implicated in tRNA, mRNA, and small interfering RNA (siRNA) maturation that when mutated, gives rise to neurodegenerative disease (Schaffer et al 2014). Also, the general pre-mRNA splicing factors, such as PRPF3, PRPF8, and PRPF31, are substantial contributors to isolated retinitis pigmentosa when rendered dysfunctional, yet mutation-bearing individuals do not display syndromic features (McKie et al 2001;Vithana et al 2001;Chakarova et al 2002;Liu and Zack 2013). Although rpl10 is expressed widely in the zebrafish embryo (Thisse and Thisse 2004), but with augmented expression levels in the developing zebrafish head in comparison to the posterior region, our data indicate that central nervous system defects are likely due to altered quantitative, and potentially qualitative, translational activity restricted to the anterior structures.…”

Section: Resultsmentioning

confidence: 99%

A Novel Ribosomopathy Caused by Dysfunction of RPL10 Disrupts Neurodevelopment and Causes X-Linked Microcephaly in Humans

et al. 2014

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Neurodevelopmental defects in humans represent a clinically heterogeneous group of disorders. Here, we report the genetic and functional dissection of a multigenerational pedigree with an X-linked syndromic disorder hallmarked by microcephaly, growth retardation, and seizures. Using an X-linked intellectual disability (XLID) next-generation sequencing diagnostic panel, we identified a novel missense mutation in the gene encoding 60S ribosomal protein L10 (RPL10), a locus associated previously with autism spectrum disorders (ASD); the p.K78E change segregated with disease under an X-linked recessive paradigm while, consistent with causality, carrier females exhibited skewed X inactivation. To examine the functional consequences of the p.K78E change, we modeled RPL10 dysfunction in zebrafish. We show that endogenous rpl10 expression is augmented in anterior structures, and that suppression decreases head size in developing morphant embryos, concomitant with reduced bulk translation and increased apoptosis in the brain. Subsequently, using in vivo complementation, we demonstrate that p.K78E is a loss-of-function variant. Together, our findings suggest that a mutation within the conserved N-terminal end of RPL10, a protein in close proximity to the peptidyl transferase active site of the 60S ribosomal subunit, causes severe defects in brain formation and function. N EURODEVELOPMENTAL defects in humans represent a diagnostic challenge. Displaying marked phenotypic overlap, examples include autism spectrum disorders (ASD), intellectual disability (ID), microcephaly, and seizures; in some instances, common genetic defects can underscore each of these clinical entities. For example, mutations in the voltage-gated sodium channel Na v 1.2 encoded by SCN2A are associated with the manifestation of early infantile epilepsy (Sugawara et al. 2001). However, recent exome sequencing studies have also identified SCN2A mutations as rare contributors to disease in autism cohorts, thereby expanding the phenotypic spectrum underscored by Na v 1.2 channel dysfunction (Sanders et al. 2012). A gender bias of 1.3-1.4 males to 1 female with a neurodevelopmental disorder has complicated further our mechanistic understanding of such defects (Leonard and Wen 2002;Ellison et al. 2013). One obvious explanation for an unbalanced representation of the sexes among individuals with a structural or functional brain defect is an abundance of developmentally important genes on the X chromosome. To date, .100 genes have been associated with ASD, ID, microcephaly, or seizures primarily in hemizygous males and, to some extent, their carrier mothers (De Brouwer et al. 2007;Tarpey et al. 2009;Lubs et al. 2012).Here, we report the genetic dissection of a novel form of X-linked human genetic disease characterized by microcephaly, seizures, growth retardation, and hypotonia. Combined genetic, functional, and biochemical assays suggest that a missense mutation in RPL10, a component of the 60S large ribosomal subunit, can cause syndromic central nervo...

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Section: Resultsmentioning

confidence: 99%

A Novel Ribosomopathy Caused by Dysfunction of RPL10 Disrupts Neurodevelopment and Causes X-Linked Microcephaly in Humans

et al. 2014

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“…Alternative splicing is a dynamically regulated process that contributes to the proteomic diversity and it is especially common for genes expressed in the nervous system, where the synthesis of protein variants determines properties of different types of neurons [24, 25]. It has been estimated that 15% of disease causing point-mutations affect pre-mRNA splicing and impaired splicing is also known to contribute to retinal degeneration [26]. In addition to the previously discovered EYS isoforms 1 and 4, we have now confirmed the existence of two shorter splicing variants, EYS isoforms 2 and 3, which are also expressed in the testis.…”

Section: Discussionmentioning

confidence: 99%

EYS Is a Protein Associated with the Ciliary Axoneme in Rods and Cones

Alfano¹,

Kruczek²,

Shah³

et al. 2016

PLoS ONE

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PurposeMutations in the EYS gene are a common cause of autosomal recessive retinitis pigmentosa (arRP), yet the role of the EYS protein in humans is presently unclear. The aim of this study was to investigate the isoform structure, expression and potential function of EYS in the mammalian retina in order to better understand its involvement in the pathogenesis of arRP.MethodsTo achieve the objective, we examined the expression of mRNA transcripts of EYS isoforms in human tissues and cell lines by RT-PCR. We also investigated the localisation of EYS in cultured cells and retinal cryo-sections by confocal fluorescence microscopy and Western blot analysis.ResultsRT-PCR analysis confirmed that EYS has at least four isoforms. In addition to the previously reported EYS isoforms 1 and 4, we present the experimental validation of two smaller variants referred to as EYS isoforms 2 and 3. All four isoforms are expressed in the human retina and Y79 cells and the short variants were additionally detected in the testis. Immunofluorescent confocal microscopy and Western blot analysis revealed that all EYS isoforms preferentially localise to the cytoplasm of Y79 and HeLa cells. Moreover, an enrichment of the endogenous protein was observed near the centrosomes in Y79 cells. Interestingly, EYS was observed at the ciliary axoneme in Y79 ciliated cells. In macaque retinal cryosections, EYS was found to localise in the region of the photoreceptor ciliary axoneme in both rods and cones as well as in the cytoplasm of the ganglion cells.ConclusionThe results obtained in this study lead us to speculate that, in photoreceptor cells, EYS could be a protein involved in maintaining the stability of the ciliary axoneme in both rods and cones. The variability of its isoform structure suggests that other roles are also possible and yet to be established.

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“…For example, the protein products of four adRP genes, PRPF3, PRPF8, PRPF31, and SNRNP200, are essential components of the U4/U6-U5 tri-snRNP complex of the spliceo-some involved in mRNA splicing (Liu and Zack 2013). The products of two less frequent causes of adRP, PRPF4 and PRPF6, are also components of this complex.…”

Section: Normal Function Of Adrp Genesmentioning

confidence: 99%

Genes and Mutations Causing Autosomal Dominant Retinitis Pigmentosa

Daiger

Bowne

Sullivan

2014

Cold Spring Harb Perspect Med

114

140

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Retinitis pigmentosa (RP) has a prevalence of approximately one in 4000; 25%–30% of these cases are autosomal dominant retinitis pigmentosa (adRP). Like other forms of inherited retinal disease, adRP is exceptionally heterogeneous. Mutations in more than 25 genes are known to cause adRP, more than 1000 mutations have been reported in these genes, clinical findings are highly variable, and there is considerable overlap with other types of inherited disease. Currently, it is possible to detect disease-causing mutations in 50%–75% of adRP families in select populations. Genetic diagnosis of adRP has advantages over other forms of RP because segregation of disease in families is a useful tool for identifying and confirming potentially pathogenic variants, but there are disadvantages too. In addition to identifying the cause of disease in the remaining 25% of adRP families, a central challenge is reconciling clinical diagnosis, family history, and molecular findings in patients and families.

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Alternative splicing and retinal degeneration

Cited by 78 publications

References 68 publications

A Novel Ribosomopathy Caused by Dysfunction of RPL10 Disrupts Neurodevelopment and Causes X-Linked Microcephaly in Humans

A Novel Ribosomopathy Caused by Dysfunction of RPL10 Disrupts Neurodevelopment and Causes X-Linked Microcephaly in Humans

EYS Is a Protein Associated with the Ciliary Axoneme in Rods and Cones

Genes and Mutations Causing Autosomal Dominant Retinitis Pigmentosa

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