The non-coding transcriptome as a dynamic regulator of cancer metastasis.

Since the discovery of microRNAs, non-coding RNAs (NC-RNAs) have increasingly attracted the attention of cancer investigators. Two classes of NC-RNAs are emerging as putative metastasis-related genes: long non-coding RNAs (lncRNAs) and small nucleolar RNAs (snoRNAs). LncRNAs orchestrate metastatic progression through several mechanisms, including the interaction with epigenetic effectors, splicing control and generation of microRNA-like molecules. In contrast, snoRNAs have been long considered "housekeeping" genes with no relevant function in cancer. However, recent evidence challenges this assumption, indicating that some snoRNAs are deregulated in cancer cells and may play a specific role in metastasis. Interestingly, snoRNAs and lncRNAs share several mechanisms of action, and might synergize with protein-coding genes to generate a specific cellular phenotype. This evidence suggests that the current paradigm of metastatic progression is incomplete. We propose that NC-RNAs are organized in complex interactive networks which orchestrate cellular phenotypic plasticity. Since plasticity is critical for cancer cell metastasis, we suggest that a molecular interactome composed by both NC-RNAs and proteins orchestrates cancer metastasis. Interestingly, expression of lncRNAs and snoRNAs can be detected in biological fluids, making them potentially useful biomarkers. NC-RNA expression profiles in human neoplasms have been associated with patients' prognosis. SnoRNA and lncRNA silencing in pre-clinical models leads to cancer cell death and/or metastasis prevention, suggesting they can be investigated as novel therapeutic targets. Based on the literature to date, we critically discuss how the NC-RNA interactome can be explored and manipulated to generate more effective diagnostic, prognostic, and therapeutic strategies for metastatic neoplasms

Biallelic variants in the ectonucleotidase ENTPD1 cause a complex neurodevelopmental disorder with intellectual disability, distinct white matter abnormalities, and spastic paraplegia.

OBJECTIVE: Human genomics established that pathogenic variation in diverse genes can underlie a single disorder. For example, hereditary spastic paraplegia (HSP) is associated with over 80 genes with frequently only few affected individuals described for each gene. Herein, we characterize a large cohort of individuals with biallelic variation in ENTPD1, a gene previously linked to spastic paraplegia 64 (MIM# 615683). METHODS: Individuals with biallelic ENTPD1 variants were recruited worldwide. Deep phenotyping and molecular characterizations were performed. RESULTS: A total of 27 individuals from 17 unrelated families were studied; additional phenotypic information was collected from published cases. Twelve novel pathogenic ENTPD1 variants are described: c.398_399delinsAA; p.(Gly133Glu), c.540del; p.(Thr181Leufs* 18), c.640del; p.(Gly216Glufs* 75), c.185T>G; p.(Leu62*), c.1531T>C; p.(*511Glnext* 100), c.967C>T; p.(Gln323*), c.414-2_414-1del, and c.146 A>G; p.(Tyr49Cys) including four recurrent variants c.1109T>A; p.(Leu370* ), c.574-6_574-3del, c.770_771del; p.(Gly257Glufs*18), and c.1041del; p.(Ile348Phefs*19). Shared disease traits include: childhood-onset, progressive spastic paraplegia, intellectual disability (ID), dysarthria, and white matter abnormalities. In vitro assays demonstrate that ENTPD1 expression and function are impaired and that c.574-6_574-3del causes exon skipping. Global metabolomics demonstrates ENTPD1 deficiency leads to impaired nucleotide, lipid, and energy metabolism. INTERPRETATION: The ENTPD1 locus trait consists of childhood disease-onset, ID, progressive spastic paraparesis, dysarthria, dysmorphisms, and white matter abnormalities with some individuals showing neurocognitive regression. Investigation of an allelic series of ENTPD1: i) expands previously described features of ENTPD1-related neurological disease, ii) highlights the importance of genotype-driven deep phenotyping, iii) documents the need for global collaborative efforts to characterize rare AR disease traits, and iv) provides insights into the disease trait neurobiology. This article is protected by copyright. All rights reserved