Extended extraocular phenotype of PROM1 mutation in kindreds with known autosomal dominant macular dystrophy

Arrigoni, Francesca; Matarı́n, Mar; Thompson, Pamela J.; Michaelides, Michel; McClements, Michelle E.; Redmond, Elizabeth; Clarke, L.; Ellins, Elizabeth A; Mohamed, Saifullah; Pavord, Ian D.; Hunt, David M.; Moore, Anthony T.; Halcox, Julian; Sisodiya, Sanjay M.

doi:10.1038/ejhg.2010.147

Cited by 24 publications

(23 citation statements)

References 42 publications

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“…Dominant CORD is also associated with missense mutations in GUCY2D (guanylate cyclase 1) (reviewed in [32], CRX (cone-rod otx-like photoreceptor homeobox transcription factor) [33]–[35], AIPL1 (arylhydrocarbon-interacting receptor protein-like 1) [36]–[38], and PROM1 (Prominin 1) [39], [40]. Proteins encoded by these genes have very diverse functions, yet null mutations of these genes are associated with recessive RP or LCA suggesting expression is vital for photoreceptor survival.…”

Section: Discussionmentioning

confidence: 99%

RNAi-Mediated Gene Suppression in a GCAP1(L151F) Cone-Rod Dystrophy Mouse Model

Jiang

Boye

et al. 2013

PLoS ONE

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Dominant mutations occurring in the high-affinity Ca2+-binding sites (EF-hands) of the GUCA1A gene encoding guanylate cyclase-activating protein 1 (GCAP1) cause slowly progressing cone-rod dystrophy (CORD) in a dozen families worldwide. We developed a nonallele-specific adeno-associated virus (AAV)-based RNAi knockdown strategy to rescue the retina degeneration caused by GCAP1 mutations. We generated three genomic transgenic mouse lines expressing wildtype (WT) and L151F mutant mouse GCAP1 with or without a C-terminal GFP fusion. Under control of endogenous regulatory elements, the transgenes were expressed specifically in mouse photoreceptors. GCAP1(L151F) and GCAP1(L151F)-GFP transgenic mice presented with a late onset and slowly progressive photoreceptor degeneration, similar to that observed in human GCAP1-CORD patients. Transgenic expression of WT GCAP1-EGFP in photoreceptors had no adverse effect. Toward therapy development, a highly effective anti-mGCAP1 shRNA, mG1hp4, was selected from four candidate shRNAs using an in-vitro screening assay. Subsequently a self-complementary (sc) AAV serotype 2/8 expressing mG1hp4 was delivered subretinally to GCAP1(L151F)-GFP transgenic mice. Knockdown of the GCAP1(L151F)-GFP transgene product was visualized by fluorescence live imaging in the scAAV2/8-mG1hp4-treated retinas. Concomitant with the mutant GCAP1-GFP fusion protein, endogenous GCAP1 decreased as well in treated retinas. We propose nonallele-specific RNAi knockdown of GCAP1 as a general therapeutic strategy to rescue any GCAP1-based dominant cone-rod dystrophy in human patients.

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Section: Discussionmentioning

confidence: 99%

RNAi-Mediated Gene Suppression in a GCAP1(L151F) Cone-Rod Dystrophy Mouse Model

Jiang

Boye

et al. 2013

PLoS ONE

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“…A reclassification may be required based on a detailed clinical examination of family members. Since extraocular phenotypes have been described in some patients with the recurrent PROM1 mutation, this finding may have clinical implications [76]. …”

Section: Sequence and Copy Number Variationsmentioning

confidence: 99%

Mutations in Splicing Factor Genes Are a Major Cause of Autosomal Dominant Retinitis Pigmentosa in Belgian Families

et al. 2017

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PurposeAutosomal dominant retinitis pigmentosa (adRP) is characterized by an extensive genetic heterogeneity, implicating 27 genes, which account for 50 to 70% of cases. Here 86 Belgian probands with possible adRP underwent genetic testing to unravel the molecular basis and to assess the contribution of the genes underlying their condition.MethodsMutation detection methods evolved over the past ten years, including mutation specific methods (APEX chip analysis), linkage analysis, gene panel analysis (Sanger sequencing, targeted next-generation sequencing or whole exome sequencing), high-resolution copy number screening (customized microarray-based comparative genomic hybridization). Identified variants were classified following American College of Medical Genetics and Genomics (ACMG) recommendations.ResultsMolecular genetic screening revealed mutations in 48/86 cases (56%). In total, 17 novel pathogenic mutations were identified: four missense mutations in RHO, five frameshift mutations in RP1, six mutations in genes encoding spliceosome components (SNRNP200, PRPF8, and PRPF31), one frameshift mutation in PRPH2, and one frameshift mutation in TOPORS. The proportion of RHO mutations in our cohort (14%) is higher than reported in a French adRP population (10.3%), but lower than reported elsewhere (16.5–30%). The prevalence of RP1 mutations (10.5%) is comparable to other populations (3.5%-10%). The mutation frequency in genes encoding splicing factors is unexpectedly high (altogether 19.8%), with PRPF31 the second most prevalent mutated gene (10.5%). PRPH2 mutations were found in 4.7% of the Belgian cohort. Two families (2.3%) have the recurrent NR2E3 mutation p.(Gly56Arg). The prevalence of the recurrent PROM1 mutation p.(Arg373Cys) was higher than anticipated (3.5%).ConclusionsOverall, we identified mutations in 48 of 86 Belgian adRP cases (56%), with the highest prevalence in RHO (14%), RP1 (10.5%) and PRPF31 (10.5%). Finally, we expanded the molecular spectrum of PRPH2, PRPF8, RHO, RP1, SNRNP200, and TOPORS-associated adRP by the identification of 17 novel mutations.

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“…PROM1 mutations are harbored in the populations suffering from retinitis pigmentosa, macular degeneration and cone-rod retinal dystrophy (Maw et al, 2000, Michaelides et al, 2010, Permanyer et al, 2010, Yang et al, 2008, Zhang et al, 2007). In addition, reduced adhesion abilities and increased cell damages were detected in the peripheral endothelial cells that harbor CD133 missense mutation (Arrigoni et al, 2011). …”

Section: Introductionmentioning

confidence: 99%

CD133 as a regulator of cancer metastasis through the cancer stem cells

Liou

2019

The International Journal of Biochemistry & Cell Biology

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Cancer stem cells are the cancer cells that have abilities to self-renew, differentiate into defined progenies, and initiate and maintain tumor growth. They also contribute to cancer metastasis and therapeutic resistance, both of which are the major causes of cancer mortality. Among the reported makers of the cancer stem cells, CD133 is the most well-known marker for isolating and studying cancer stem cells in different types of cancer. The CD133high population of cancer cells are not only capable of self-renewal, proliferation, but also highly metastatic and resistant to therapy. Despite very limited information on physiological functions of CD133, many ongoing studies are aimed to reveal the mechanisms that CD133 utilizes to modulate cancer dissemination and drug resistance with a long-term goal for bringing down the number of cancer deaths. In this review, in addition to the regulation of CD133, and its involvement in cancer initiation, and development, the recent updates on how CD133 modulates cancer dissemination, and therapeutic resistance are provided. The key signaling pathways that are upstream or downstream of CD133 during these processes are summarized. A comprehensive understanding of CD133-mediated cancer initiation, development, and dissemination through its pivotal role in cancer stem cells will offer new strategies in cancer therapy.

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Extended extraocular phenotype of PROM1 mutation in kindreds with known autosomal dominant macular dystrophy

Cited by 24 publications

References 42 publications

RNAi-Mediated Gene Suppression in a GCAP1(L151F) Cone-Rod Dystrophy Mouse Model

RNAi-Mediated Gene Suppression in a GCAP1(L151F) Cone-Rod Dystrophy Mouse Model

Mutations in Splicing Factor Genes Are a Major Cause of Autosomal Dominant Retinitis Pigmentosa in Belgian Families

CD133 as a regulator of cancer metastasis through the cancer stem cells

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