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      Non-Syndromic Intellectual Disability and Its Pathways: A Long Noncoding RNA Perspective

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          Abstract

          Non-syndromic intellectual disability (NS-ID or idiopathic) is a complex neurodevelopmental disorder that represents a global health issue. Although many efforts have been made to characterize it and distinguish it from syndromic intellectual disability (S-ID), the highly heterogeneous aspect of this disorder makes it difficult to understand its etiology. Long noncoding RNAs (lncRNAs) comprise a large group of transcripts that can act through various mechanisms and be involved in important neurodevelopmental processes. In this sense, comprehending the roles they play in this intricate context is a valuable way of getting new insights about how NS-ID can arise and develop. In this review, we attempt to bring together knowledge available in the literature about lncRNAs involved with molecular and cellular pathways already described in intellectual disability and neural function, to better understand their relevance in NS-ID and the regulatory complexity of this disorder.

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          Most cited references186

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          Long noncoding RNA as modular scaffold of histone modification complexes.

          Long intergenic noncoding RNAs (lincRNAs) regulate chromatin states and epigenetic inheritance. Here, we show that the lincRNA HOTAIR serves as a scaffold for at least two distinct histone modification complexes. A 5' domain of HOTAIR binds polycomb repressive complex 2 (PRC2), whereas a 3' domain of HOTAIR binds the LSD1/CoREST/REST complex. The ability to tether two distinct complexes enables RNA-mediated assembly of PRC2 and LSD1 and coordinates targeting of PRC2 and LSD1 to chromatin for coupled histone H3 lysine 27 methylation and lysine 4 demethylation. Our results suggest that lincRNAs may serve as scaffolds by providing binding surfaces to assemble select histone modification enzymes, thereby specifying the pattern of histone modifications on target genes.
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            Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2.

            Rett syndrome (RTT, MIM 312750) is a progressive neurodevelopmental disorder and one of the most common causes of mental retardation in females, with an incidence of 1 in 10,000-15,000 (ref. 2). Patients with classic RTT appear to develop normally until 6-18 months of age, then gradually lose speech and purposeful hand use, and develop microcephaly, seizures, autism, ataxia, intermittent hyperventilation and stereotypic hand movements. After initial regression, the condition stabilizes and patients usually survive into adulthood. As RTT occurs almost exclusively in females, it has been proposed that RTT is caused by an X-linked dominant mutation with lethality in hemizygous males. Previous exclusion mapping studies using RTT families mapped the locus to Xq28 (refs 6,9,10,11). Using a systematic gene screening approach, we have identified mutations in the gene (MECP2 ) encoding X-linked methyl-CpG-binding protein 2 (MeCP2) as the cause of some cases of RTT. MeCP2 selectively binds CpG dinucleotides in the mammalian genome and mediates transcriptional repression through interaction with histone deacetylase and the corepressor SIN3A (refs 12,13). In 5 of 21 sporadic patients, we found 3 de novo missense mutations in the region encoding the highly conserved methyl-binding domain (MBD) as well as a de novo frameshift and a de novo nonsense mutation, both of which disrupt the transcription repression domain (TRD). In two affected half-sisters of a RTT family, we found segregation of an additional missense mutation not detected in their obligate carrier mother. This suggests that the mother is a germline mosaic for this mutation. Our study reports the first disease-causing mutations in RTT and points to abnormal epigenetic regulation as the mechanism underlying the pathogenesis of RTT.
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              Wnt/β-catenin signaling and disease.

              The WNT signal transduction cascade controls myriad biological phenomena throughout development and adult life of all animals. In parallel, aberrant Wnt signaling underlies a wide range of pathologies in humans. In this Review, we provide an update of the core Wnt/β-catenin signaling pathway, discuss how its various components contribute to disease, and pose outstanding questions to be addressed in the future. Copyright © 2012 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Noncoding RNA
                Noncoding RNA
                ncrna
                Non-Coding RNA
                MDPI
                2311-553X
                11 March 2021
                March 2021
                : 7
                : 1
                : 22
                Affiliations
                [1 ]Department of Genetics at the Ribeirão Preto Medical School, University of São Paulo, Avenida Bandeirantes 3900, Monte Alegre, Ribeirão Preto, São Paulo 14049-900, Brazil; isabelaib@ 123456usp.br (I.I.B.); leao.vitorleao@ 123456alumni.usp.br (V.L.); jessica.santis@ 123456usp.br (J.O.S.); reginaldoallves@ 123456usp.br (R.C.A.R.); daniellebrotto@ 123456alumni.usp.br (D.B.B.); camilabaldin.s@ 123456usp.br (C.B.S.); adamo@ 123456usp.br (Á.D.D.S.); gamolf@ 123456fmrp.usp.br (G.A.M.)
                [2 ]National Institute of Science and Technology in Stem Cell and Cell Therapy and Center for Cell Based Therapy, Ribeirão Preto Medical School, University of São Paulo, Rua Tenente Catão Roxo, 2501, Monte Alegre, Ribeirão Preto 14051-140, Brazil
                [3 ]Center for Integrative Systems Biology-CISBi, NAP/USP, Ribeirão Preto Medical School, University of São Paulo, Rua Catão Roxo, 2501, Monte Alegre, Ribeirão Preto 14051-140, Brazil
                [4 ]Department of Medicine at the Midwest State University of Paraná-UNICENTRO, and Guarapuava Institute for Cancer Research, Rua Fortim Atalaia, 1900, Cidade dos Lagos, Guarapuava 85100-000, Brazil
                Author notes
                [* ]Correspondence: wilsonjr@ 123456usp.br ; Tel.: +55-16-3315-3293
                Author information
                https://orcid.org/0000-0003-0984-8959
                https://orcid.org/0000-0001-9364-2886
                Article
                ncrna-07-00022
                10.3390/ncrna7010022
                8005948
                4a0663d9-0a55-4081-81a1-3a5d9e56be9e
                © 2021 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 12 November 2020
                : 07 December 2020
                Categories
                Review

                long noncoding rna,non-syndromic intellectual disability,molecular and cellular pathways,neurodevelopment,neural function

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