Description of Two Siblings with Apparently Severe CEP290 Mutations and Unusually Mild Retinal Disease Unrelated to Basal Exon Skipping or Nonsense-Associated Altered Splicing

Barny, Iris; Perrault, Isabelle; Rio, Marlène; Dollfus, Hélène; Defoort‐Dhellemmes, Sabine; Kaplan, Josseline; Rozet, Jean–Michel; Gérard, Xavier

doi:10.1007/978-3-030-27378-1_31

Cited by 4 publications

(8 citation statements)

References 12 publications

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“…This in-frame exon has been reported to undergo endogenous basal exon skipping in fibroblasts [20], producing a minimal loss of the microtubule binding domain. Yet, consistent with tissue variability of CEP290 pre-mRNA splicing [10,21,33,47], RT-PCR analysis of hURECs from the patient harboring elongated cilia showed no skipping of exon 41, Western blot analysis and immunocytochemistry detected no CEP290. Furthermore, siRNA-mediated knockdown of CEP290 led to elongated cilia [46].…”

Section: Discussionmentioning

confidence: 64%

“…The PTC-free mRNA product was detected both in patient and control cells, though with minimal amounts in controls. This observation indicates ( i ) that CEP290 exon 36, like exons 6, 10, 18, 32, 41, 46, and 51 [20,21,33], undergoes endogenous non-canonical basal exon skipping in wild-type skin fibroblasts and ( ii ) that the A to T transversion at position c.4723 enhances skipping. In silico analysis which predicted that the variation lies within an ESE indicates that skipping augmentation is promoted through nonsense-associated altered splicing.…”

Section: Discussionmentioning

confidence: 98%

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AON-Mediated Exon Skipping to Bypass Protein Truncation in Retinal Dystrophies Due to the Recurrent CEP290 c.4723A > T Mutation. Fact or Fiction?

Barny

Perrault

Michel

et al. 2019

Genes

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Mutations in CEP290 encoding a centrosomal protein important to cilia formation cause a spectrum of diseases, from isolated retinal dystrophies to multivisceral and sometimes embryo–lethal ciliopathies. In recent years, endogenous and/or selective non-canonical exon skipping of mutant exons have been documented in attenuated retinal disease cases. This observation led us to consider targeted exon skipping to bypass protein truncation resulting from a recurrent mutation in exon 36 (c.4723A > T, p.Lys1575*) causing isolated retinal ciliopathy. Here, we report two unrelated individuals (P1 and P2), carrying the mutation in homozygosity but affected with early-onset severe retinal dystrophy and congenital blindness, respectively. Studying skin-derived fibroblasts, we observed basal skipping and nonsense associated–altered splicing of exon 36, producing low (P1) and very low (P2) levels of CEP290 products. Consistent with a more severe disease, fibroblasts from P2 exhibited reduced ciliation compared to P1 cells displaying normally abundant cilia; both lines presented however significantly elongated cilia, suggesting altered axonemal trafficking. Antisense oligonucleotides (AONs)-mediated skipping of exon 36 increased the abundance of the premature termination codon (PTC)-free mRNA and protein, reduced axonemal length and improved cilia formation in P2 but not in P1 expressing higher levels of skipped mRNA, questioning AON-mediated exon skipping to treat patients carrying the recurrent c.4723A > T mutation.

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Section: Discussionmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 98%

AON-Mediated Exon Skipping to Bypass Protein Truncation in Retinal Dystrophies Due to the Recurrent CEP290 c.4723A > T Mutation. Fact or Fiction?

Barny

Perrault

Michel

et al. 2019

Genes

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“…Thus, CEP290-LCA mutations likely give rise to near full-length proteins whose expression levels may be predictive of disease severity. However, CEP290 mutations that are severe in one family are sometimes mild in another 23 , and even intrafamilial variability has been observed for CEP290- and other forms of LCA 24–26 . Genetic modifiers are often evoked to explain these types of variability, as well as the overall pleiotropy of LCA 2,3,12 .…”

Section: Introductionmentioning

confidence: 99%

Genetic modifiers of Cep290-mediated retinal degeneration

Meyer

Whitmore

Burnight

et al. 2022

Preprint

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Mutations in CEP290 cause up to 30% of cases of Leber congenital amaurosis (LCA), a severe childhood blindness resulting from abnormalities in the photoreceptor connecting cilia that lead to rapid retinal degeneration. Like many genetic diseases, CEP290-LCA has considerable variable expressivity, indicating the presence of other factors that influence phenotypic outcome. Here, we have undertaken a phenotype-driven approach in mice to identify genetic modifiers of CEP290-mediated retinal degeneration through backcrosses and intercrosses between BXD24-Cep290rd16 mice and the genetically distinct inbred CAST strain to introduce genetic variation. Optical coherence tomography was used to quantitatively measure retinal thickness as a surrogate indication of photoreceptor degeneration in the resulting rd16-mutant mice. It was readily apparent that CEP290-mediated retinal degeneration in the resulting mice is sensitive to genetic background, with some mice exhibiting relatively thick laminated retinas and others having thin retinas with advanced disease. Quantitative trait locus (QTL) analysis identified multiple genomic loci capable of influencing the retinal degeneration phenotype in Cep290-mutant mice that together account for 71.7% of the phenotypic variation in retinal thickness observed in our population. Following the QTL analysis, two suppressor loci were studied in detail through a combination of physical and molecular approaches to narrow the critical region for each QTL and identify the probable causative genetic variations.

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“…One possibility is that different genetic backgrounds may contribute modifier genes that compensate or alter CEP290 deficiency ( Coppieters et al, 2010 ; Gorden et al, 2008 ; Lessieur et al, 2019 ; Ramsbottom et al, 2020 ; Rao et al, 2016 ). Another possibility is that basal exon skipping or nonsense-associated alternative splicing may promote bypassing CEP290 mutations and the expression of functional CEP290 protein ( Barny et al, 2019 ; Littink et al, 2010 ). CEP290 protein dosage; i.e.…”

Section: Introductionmentioning

confidence: 99%

“…the amount of CEP290 protein retaining all or some of the full-length functionality, has also been proposed to determine the range and severity of CEP290 deficiency phenotypes ( Drivas et al, 2015 ). Despite these efforts to understand phenotypic variation associated with CEP290 mutations, questions remain about mechanisms of CEP290 phenotype expression ( Barny et al, 2019 ; Littink et al, 2010 ). Several recent reports indicate that gene inactivation can activate genetic compensation mechanisms that contribute to phenotypic variability or the absence of phenotypes in diverse animal models ( Buglo et al, 2020 ; Ma et al, 2019 ; Rossi et al, 2015 ; Serobyan et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Genetic compensation for cilia defects in cep290 mutants by upregulation of cilia-associated small GTPases

Cárdenas-Rodríguez

Austin‐Tse

Bergboer

et al. 2021

Journal of Cell Science

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Mutations in CEP290, a large multidomain coiled coil protein, are associated with multiple cilia-associated syndromes. Over 130 CEP290 mutations have been linked to a wide spectrum of human ciliopathies, raising the question of how mutations in a single gene cause different disease syndromes. In zebrafish the expressivity of cep290 deficiencies were linked to the type of genetic ablation: acute cep290 morpholino knockdown caused severe cilia-related phenotypes while defects in a Crispr/Cas9 genetic mutant were restricted to photoreceptor defects. Here we show that milder phenotypes in genetic mutants were associated with upregulation of genes encoding the cilia-associated small GTPases arl3, arl13b, and unc119b. Upregulation of UNC119b was also observed in urine-derived renal epithelial cells from human JBTS CEP290 patients. Ectopic expression of arl3, arl13b and unc119b in cep290 morphant zebrafish embryos rescued Kupffer's vesicle cilia and partially rescued photoreceptor outer segment defects. The results suggest that genetic compensation by upregulation of genes involved in a common subcellular process, lipidated protein trafficking to cilia, may be a conserved mechanism contributing to genotype-phenotype variations observed in CEP290 deficiencies.

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Description of Two Siblings with Apparently Severe CEP290 Mutations and Unusually Mild Retinal Disease Unrelated to Basal Exon Skipping or Nonsense-Associated Altered Splicing

Cited by 4 publications

References 12 publications

AON-Mediated Exon Skipping to Bypass Protein Truncation in Retinal Dystrophies Due to the Recurrent CEP290 c.4723A > T Mutation. Fact or Fiction?

AON-Mediated Exon Skipping to Bypass Protein Truncation in Retinal Dystrophies Due to the Recurrent CEP290 c.4723A > T Mutation. Fact or Fiction?

Genetic modifiers of Cep290-mediated retinal degeneration

Genetic compensation for cilia defects in cep290 mutants by upregulation of cilia-associated small GTPases

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