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      New gene discoveries in skeletal diseases with short stature

      review-article
      Author(s): 1 , 2 , 3 , 4 , 1 , 2 , 3 , 4 , 5
      Publication date (Electronic):
      Journal: Endocrine Connections
      Publisher: Bioscientifica Ltd

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          Abstract

          In the last decade, the widespread use of massively parallel sequencing has considerably boosted the number of novel gene discoveries in monogenic skeletal diseases with short stature. Defects in genes playing a role in the maintenance and function of the growth plate, the site of longitudinal bone growth, are a well-known cause of skeletal diseases with short stature. However, several genes involved in extracellular matrix composition or maintenance as well as genes partaking in various biological processes have also been characterized. This review aims to describe the latest genetic findings in spondyloepiphyseal dysplasias, spondyloepimetaphyseal dysplasias, and some monogenic forms of isolated short stature. Some examples of novel genetic mechanisms leading to skeletal conditions with short stature will be described. Strategies on how to successfully characterize novel skeletal phenotypes with short stature and genetic approaches to detect and validate novel gene-disease correlations will be discussed in detail. In summary, we review the latest gene discoveries underlying skeletal diseases with short stature and emphasize the importance of characterizing novel molecular mechanisms for genetic counseling, for an optimal management of the disease, and for therapeutic innovations.

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          A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity.

          Martin Jinek, Krzysztof Chylinski, Ines Fonfara … (2012)
          Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated (Cas) systems provide bacteria and archaea with adaptive immunity against viruses and plasmids by using CRISPR RNAs (crRNAs) to guide the silencing of invading nucleic acids. We show here that in a subset of these systems, the mature crRNA that is base-paired to trans-activating crRNA (tracrRNA) forms a two-RNA structure that directs the CRISPR-associated protein Cas9 to introduce double-stranded (ds) breaks in target DNA. At sites complementary to the crRNA-guide sequence, the Cas9 HNH nuclease domain cleaves the complementary strand, whereas the Cas9 RuvC-like domain cleaves the noncomplementary strand. The dual-tracrRNA:crRNA, when engineered as a single RNA chimera, also directs sequence-specific Cas9 dsDNA cleavage. Our study reveals a family of endonucleases that use dual-RNAs for site-specific DNA cleavage and highlights the potential to exploit the system for RNA-programmable genome editing.
          Article 0 comments Cited 3688 times – based on 0 reviews     Review now
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            The zebrafish reference genome sequence and its relationship to the human genome.

            Kerstin Howe, Matthew D. Clark, Carlos F Torroja … (2013)
            Zebrafish have become a popular organism for the study of vertebrate gene function. The virtually transparent embryos of this species, and the ability to accelerate genetic studies by gene knockdown or overexpression, have led to the widespread use of zebrafish in the detailed investigation of vertebrate gene function and increasingly, the study of human genetic disease. However, for effective modelling of human genetic disease it is important to understand the extent to which zebrafish genes and gene structures are related to orthologous human genes. To examine this, we generated a high-quality sequence assembly of the zebrafish genome, made up of an overlapping set of completely sequenced large-insert clones that were ordered and oriented using a high-resolution high-density meiotic map. Detailed automatic and manual annotation provides evidence of more than 26,000 protein-coding genes, the largest gene set of any vertebrate so far sequenced. Comparison to the human reference genome shows that approximately 70% of human genes have at least one obvious zebrafish orthologue. In addition, the high quality of this genome assembly provides a clearer understanding of key genomic features such as a unique repeat content, a scarcity of pseudogenes, an enrichment of zebrafish-specific genes on chromosome 4 and chromosomal regions that influence sex determination.
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              Non-coding RNAs in human disease.

              Manel Esteller (2011)
              The relevance of the non-coding genome to human disease has mainly been studied in the context of the widespread disruption of microRNA (miRNA) expression and function that is seen in human cancer. However, we are only beginning to understand the nature and extent of the involvement of non-coding RNAs (ncRNAs) in disease. Other ncRNAs, such as PIWI-interacting RNAs (piRNAs), small nucleolar RNAs (snoRNAs), transcribed ultraconserved regions (T-UCRs) and large intergenic non-coding RNAs (lincRNAs) are emerging as key elements of cellular homeostasis. Along with microRNAs, dysregulation of these ncRNAs is being found to have relevance not only to tumorigenesis, but also to neurological, cardiovascular, developmental and other diseases. There is great interest in therapeutic strategies to counteract these perturbations of ncRNAs.
              Article 0 comments Cited 979 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Endocr Connect
                Journal ID (iso-abbrev): Endocr Connect
                Journal ID (hwp): EC
                Title: Endocrine Connections
                Publisher: Bioscientifica Ltd (Bristol )
                ISSN (Electronic): 2049-3614
                Publication date (Electronic): 07 April 2021
                Publication date Collection: 01 May 2021
                Volume: 10
                Issue: 5
                Pages: R160-R174
                Affiliations
                [1 ]Department of Molecular Medicine and Surgery and Center for Molecular Medicine , Karolinska Institutet, Stockholm, Sweden
                [2 ]Folkhälsan Institute of Genetics , University of Helsinki, Helsinki, Finland
                [3 ]Children’s Hospital , University of Helsinki and Helsinki University Hospital, Helsinki, Finland
                [4 ]Research Program for Clinical and Molecular Metabolism , University of Helsinki, Helsinki, Finland
                [5 ]Department of Clinical Genetics , Karolinska University Hospital, Stockholm, Sweden
                Author notes
                Correspondence should be addressed to O Mäkitie: outi.makitie@ 123456helsinki.fi
                Article
                Publisher ID: EC-21-0083
                DOI: 10.1530/EC-21-0083
                PMC ID: 8183621
                PubMed ID: 33830070
                SO-VID: 8f71a70c-c345-45d8-9ca0-13aa9b42349a
                Copyright © © The authors
                License:

                This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

                History
                Date received : 25 February 2021
                Date accepted : 07 April 2021
                Categories
                Subject: Review

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