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      Exome Sequencing and Linkage Analysis Identified Tenascin-C ( TNC) as a Novel Causative Gene in Nonsyndromic Hearing Loss

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          Abstract

          In this study, a five-generation Chinese family (family F013) with progressive autosomal dominant hearing loss was mapped to a critical region spanning 28.54 Mb on chromosome 9q31.3-q34.3 by linkage analysis, which was a novel DFNA locus, assigned as DFNA56. In this interval, there were 398 annotated genes. Then, whole exome sequencing was applied in three patients and one normal individual from this family. Six single nucleotide variants and two indels were found co-segregated with the phenotypes. Then using mass spectrum (Sequenom, Inc.) to rank the eight sites, we found only the TNC gene be co-segregated with hearing loss in 53 subjects of F013. And this missense mutation (c.5317G>A, p.V1773M ) of TNC located exactly in the critical linked interval. Further screening to the coding region of this gene in 587 subjects with nonsyndromic hearing loss (NSHL) found a second missense mutation, c.5368A>T (p. T1796S), co-segregating with phenotype in the other family. These two mutations located in the conserved region of TNC and were absent in the 387 normal hearing individuals of matched geographical ancestry. Functional effects of the two mutations were predicted using SIFT and both mutations were deleterious. All these results supported that TNC may be the causal gene for the hearing loss inherited in these families. TNC encodes tenascin-C, a member of the extracellular matrix (ECM), is present in the basilar membrane (BM), and the osseous spiral lamina of the cochlea. It plays an important role in cochlear development. The up-regulated expression of TNC gene in tissue repair and neural regeneration was seen in human and zebrafish, and in sensory receptor recovery in the vestibular organ after ototoxic injury in birds. Then the absence of normal tenascin-C was supposed to cause irreversible injuries in cochlea and caused hearing loss.

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          Most cited references12

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          The tenascin family of ECM glycoproteins: structure, function, and regulation during embryonic development and tissue remodeling.

          The determination of animal form depends on the coordination of events that lead to the morphological patterning of cells. This epigenetic view of development suggests that embryonic structures arise as a consequence of environmental influences acting on the properties of cells, rather than an unfolding of a completely genetically specified and preexisting invisible pattern. Specialized cells of developing multicellular organisms are surrounded by a complex extracellular matrix (ECM), comprised largely of different collagens, proteoglycans, and glycoproteins. This ECM is a substrate for tissue morphogenesis, lends support and flexibility to mature tissues, and acts as an epigenetic informational entity in the sense that it transduces and integrates intracellular signals via distinct cell surface receptors. Consequently, ECM-receptor interactions have a profound influence on major cellular programs including growth, differentiation, migration, and survival. In contrast to many other ECM proteins, the tenascin (TN) family of glycoproteins (TN-C, TN-R, TN-W, TN-X, and TN-Y) display highly restricted and dynamic patterns of expression in the embryo, particularly during neural development, skeletogenesis, and vasculogenesis. These molecules are reexpressed in the adult during normal processes such as wound healing, nerve regeneration, and tissue involution, and in pathological states including vascular disease, tumorigenesis, and metastasis. In concert with a multitude of associated ECM proteins and cell surface receptors that include members of the integrin family, TN proteins impart contrary cellular functions, depending on their mode of presentation (i.e., soluble or substrate-bound) and the cell types and differentiation states of the target tissues. Expression of tenascins is regulated by a variety of growth factors, cytokines, vasoactive peptides, ECM proteins, and biomechanical factors. The signals generated by these factors converge on particular combinations of cis-regulatory elements within the recently identified TN gene promoters via specific transcriptional activators or repressors. Additional complexity in regulating TN gene expression is achieved through alternative splicing, resulting in variants of TN polypeptides that exhibit different combinations of functional protein domains. In this review, we discuss some of the recent advances in TN biology that provide insights into the complex way in which the ECM is regulated and how it functions to regulate tissue morphogenesis and gene expression. Copyright 2000 Wiley-Liss, Inc.
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            Identification of mutations in the COL4A5 collagen gene in Alport syndrome.

            X-linked Alport syndrome is a hereditary glomerulonephritis in which progressive loss of kidney function is often accompanied by progressive loss of hearing. Ultrastructural defects in glomerular basement membranes (GBM) of Alport syndrome patients implicate an altered structural protein as the cause of nephritis. The product of COL4A5, the alpha 5(IV) collagen chain, is a specific component of GBM within the kidney, and the gene maps to the same X chromosomal region as does Alport syndrome. Three structural aberrations were found in COL4A5, in intragenic deletion, a Pst I site variant, and an uncharacterized abnormality, which appear to cause nephritis and deafness, with allele-specific severity, in three Alport syndrome kindreds in Utah.
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              Whole exome sequencing and homozygosity mapping identify mutation in the cell polarity protein GPSM2 as the cause of nonsyndromic hearing loss DFNB82.

              Massively parallel sequencing of targeted regions, exomes, and complete genomes has begun to dramatically increase the pace of discovery of genes responsible for human disorders. Here we describe how exome sequencing in conjunction with homozygosity mapping led to rapid identification of the causative allele for nonsyndromic hearing loss DFNB82 in a consanguineous Palestinian family. After filtering out worldwide and population-specific polymorphisms from the whole exome sequence, only a single deleterious mutation remained in the homozygous region linked to DFNB82. The nonsense mutation leads to an early truncation of the G protein signaling modulator GPSM2, a protein that is essential for maintenance of cell polarity and spindle orientation. In the mouse inner ear, GPSM2 is localized to apical surfaces of hair cells and supporting cells and is most highly expressed during embryonic development. Identification of GPSM2 as essential to the development of normal hearing suggests dysregulation of cell polarity as a mechanism underlying hearing loss. Copyright 2010 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2013
                30 July 2013
                : 8
                : 7
                : e69549
                Affiliations
                [1 ]Department of Otorhinolaryngology, Head and Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital, Beijing, China
                [2 ]BGI-Shenzhen, Shenzhen, China
                [3 ]T-Life Research Center, Fudan University, Shanghai, China
                [4 ]Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, China
                [5 ]Department of Orthopaedic Surgery, Chinese PLA General Hospital, Beijing, China
                [6 ]BGI-Tianjin, Tianjin, China
                [7 ]School of Bioscience and Biotechnology, South China University of Technology, Guangzhou, China
                [8 ]State Key Laboratory for AgroBiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China
                [9 ]Institute of Life Sciences, Chinese PLA General Hospital, Beijing, China
                [10 ]Genetics and physiology of hearing, Neuroscience, College de France and Institute Pasteur, Paris, France
                [11 ]Department of Biology, University of Copenhagen, Copenhagen, Denmark
                Innsbruck Medical University, Austria
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: QW YZ. Performed the experiments: YZ. Analyzed the data: PZ LG JZ Jing Wang LY XJ. Contributed reagents/materials/analysis tools: DW WC LL QL BH. Wrote the paper: YZ FZ LZ. Critical reading anddiscussion of manuscript: WY XH XW NL YL CP Jun Wang HY Jian Wang QW.

                Article
                PONE-D-13-19483
                10.1371/journal.pone.0069549
                3728356
                23936043
                76380766-4128-4d17-88d5-ab71df270a4f
                Copyright @ 2013

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 11 May 2013
                : 11 June 2013
                Page count
                Pages: 8
                Funding
                This work was supported by the grants of the National Natural Science Foundation of China, Major Project, No. 81120108009 and National Natural Science Foundation of Youth Science Foundation No.81100719. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology
                Genetics
                Heredity
                Genotypes
                Linkage (Genetics)
                Phenotypes
                Human Genetics
                Autosomal Dominant
                Genetic Testing
                Genetic Mutation
                Genetic Screens
                Genetics of Disease
                Medicine
                Clinical Genetics
                Autosomal Dominant
                Otorhinolaryngology
                Otology
                Hearing Disorders
                Audiology

                Uncategorized
                Uncategorized

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