Haploinsufficiency of the miR-873/miR-876 microRNA cluster is associated with craniofacial abnormalities

Koufaris, Costas; Papagregoriou, Gregoris; Kousoulidou, Ludmila; Moutafi, Maria; Tauber, Maïthé; Jouret, Béatrice; Kieffer, Isabelle; Deltas, Constantinos; Tanteles, George A.; Anastasiadou, Violetta; Patsalis, Philippos C.; Sismani, Carolina

doi:10.1016/j.gene.2015.02.018

Cited by 14 publications

(9 citation statements)

References 24 publications

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“…Individual 20 also had a de novo in-frame deletion of five amino acids in LINGO2 (NM_001258282.1:c.1543_1557del; (p. (Pro515_Thr519del)). LINGO2 deletions have previously been reported in individuals with developmental delay, autistic behavior, and craniofacial abnormalities [48,49], and a contribution of this variant to the individual's phenotype cannot be excluded.…”

Section: Discussionmentioning

confidence: 99%

De novo variants in FBXO11 cause a syndromic form of intellectual disability with behavioral problems and dysmorphisms

et al. 2019

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Determining pathogenicity of genomic variation identified by next-generation sequencing techniques can be supported by recurrent disruptive variants in the same gene in phenotypically similar individuals. However, interpretation of novel variants in a specific gene in individuals with mild-moderate intellectual disability (ID) without recognizable syndromic features can be challenging and reverse phenotyping is often required. We describe 24 individuals with a de novo disease-causing variant in, or partial deletion of, the F-box only protein 11 gene (FBXO11, also known as VIT1 and PRMT9). FBXO11 is part of the SCF (SKP1-cullin-F-box) complex, a multi-protein E3 ubiquitin-ligase complex catalyzing the ubiquitination of proteins destined for proteasomal degradation. Twenty-two variants were identified by nextgeneration sequencing, comprising 2 in-frame deletions, 11 missense variants, 1 canonical splice site variant, and 8 nonsense or frameshift variants leading to a truncated protein or degraded transcript. The remaining two variants were identified by array-comparative genomic hybridization and consisted of a partial deletion of FBXO11. All individuals had borderline to severe ID and behavioral problems (autism spectrum disorder, attention-deficit/hyperactivity disorder, anxiety, aggression) were observed in most of them. The most relevant common facial features included a thin upper lip and a broad prominent space between the paramedian peaks of the upper lip. Other features were hypotonia and hyperlaxity of the joints. We show that de novo variants in FBXO11 cause a syndromic form of ID. The current series show the power of reverse phenotyping in the interpretation of novel genetic variances in individuals who initially did not appear to have a clear recognizable phenotype.

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Section: Discussionmentioning

confidence: 99%

De novo variants in FBXO11 cause a syndromic form of intellectual disability with behavioral problems and dysmorphisms

et al. 2019

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“…Liu et al demonstrated that when stimulated by IL-17, miR-873 promotes the activation of NF-κB and the production of inflammatory cytokines in human multiple sclerosis (16). It has also been reported that miR-873 is involved in the regulation of the Hedgehog signaling and has relevance to physiological cranial bone development (20). miR-873 is downregulated in tamoxifen-resistant breast tumor cell lines, while overexpression of miR-873 reverses the tamoxifen resistance by targeting cyclin-dependent kinase 3 (CDK3) (15).…”

Section: Discussionmentioning

confidence: 99%

miR-873 acts as a novel sensitizer of glioma cells to cisplatin by targeting Bcl-2

Xiong

Zhang

Shi

et al. 2015

International Journal of Oncology

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Treatment with cisplatin, a chemotherapeutic agent commonly used in glioma patients, often results in chemoresistance. Increasing evidence has shown that microRNAs (miRNAs) are implicated in the drug resistance of gliomas. However, the function of miR‑873 in cisplatin resistance of gliomas remains unknown. In this study, we found that many miRNAs, including miR‑873, are differentially expressed in cisplatin-resistant glioma cells compared to wild-type glioma cells. Moreover, cisplatin reduced the expression of miR‑873 in a time-dependent manner. Overexpression of miR‑873 decreased the cell proliferation, migration and invasion while increased apoptosis of cisplatin-resistant glioma cells and sensitized the cells to cisplatin-induced cell growth arrest and apoptosis. Furthermore, miR‑873 was downregulated while Bcl-2 was upregulated in the tissues of twelve high-grade glioma patients compared to seven normal brain tissues, and the miR‑873 level was negatively correlated with the Bcl-2 protein level. A luciferase reporter assay further confirmed that Bcl-2 was a direct target of miR‑873, and miR‑873 decreased the level of the Bcl-2 protein in cisplatin-resistant glioma cells. Notably, re-expression of Bcl-2 attenuated the function of miR‑873 in cisplatin-resistant glioma cells and the sensitivity of the cells to cisplatin. Taken together, these data suggest that miR‑873 might be a potential marker for cisplatin resistance and a promising sensitizer in cisplatin treatment.

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“…Although potassium channels are important in many non-neuronal tissues, we would expect that miR-873-5p effects are more relevant in their neuronal context, due to its neuronal expression, correlated with host gene LINGO2 [155]. This is further supported by the primary expression pattern of the mouse homolog of LINGO2 (which also hosts miR-873) in the central nervous system during early embryogenesis (E10) [155,166].…”

Section: Discussionmentioning

confidence: 89%

“…MicroRNA miR-873 is located within the neuronally expressed LINGO2 gene, nearby another mi-croRNA, miR-876, and the three genes have correlated expression [155]. MiR-873 has been studied or found dysregulated in a number of diverse contexts, including cancers [156][157][158][159], immune system [160,161], and pregnancy [162][163][164].…”

Section: Introductionmentioning

confidence: 99%

“…MiR-873 has been studied or found dysregulated in a number of diverse contexts, including cancers [156][157][158][159], immune system [160,161], and pregnancy [162][163][164]. There is also evidence for a neuronal function, as a heterozygous deletion of this region has been observed in an individual with craniofacial abnormalities and learning difficulties [155]. MiR-873 has also been detected differentially expressed in a memoryimpaired epileptic rat model [165].…”

Section: Introductionmentioning

confidence: 99%

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Characterisation of neuronal and autism-associated microRNAs through systems-based analysis

Williams¹

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MicroRNAs are important regulatory factors in brain development and function. DNA variations disrupting their function may contribute to neurodevelopmental disorders such as autism. Operating at the posttranscriptional level, microRNAs regulate broad yet controlled sets of target genes typically via interacting with target sites found in 3' untranslated regions of mRNA transcripts. Efforts to identify microRNAs contributing to autism risk have involved examining differences in their expression patterns, mutations that affect their function, and their interaction with autism-risk genes. However, there have yet to be any robustly replicated candidate microRNAs supported by these functional evidences. Knowing what genes a microRNA targets is a major challenge in the field, and represents an important first step in investigating their biological role and contribution to autism. A huge thank-you for my work-mates-for their company, advice, humour and encouragement that have made for friendly and welcoming offices and labs. More professionally, special thanks to Joon, Flavia, Michelle, Nivetha, Jing and Ramesh for the many insightful discussions, shared links and resources, technical advice, tips, training, help and draft-reading that have pushed this work forward. Lastly, thanks to my friends and family for many long years of support and encouragement. Especially Brent for helping me 'science' through his patient understanding, proofreading, sympathetic ear, welltimed provision of coffee and unwavering support.

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Haploinsufficiency of the miR-873/miR-876 microRNA cluster is associated with craniofacial abnormalities

Cited by 14 publications

References 24 publications

De novo variants in FBXO11 cause a syndromic form of intellectual disability with behavioral problems and dysmorphisms

De novo variants in FBXO11 cause a syndromic form of intellectual disability with behavioral problems and dysmorphisms

miR-873 acts as a novel sensitizer of glioma cells to cisplatin by targeting Bcl-2

Characterisation of neuronal and autism-associated microRNAs through systems-based analysis

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