DFNB1 Non-syndromic Hearing Impairment: Diversity of Mutations and Associated Phenotypes
The inner ear is a very complex sensory organ whose development and function depend on finely balanced interactions among diverse cell types. The many different kinds of inner ear supporting cells play the essential roles of providing physical and physiological support to sensory hair cells and of m...
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doaj-5baa544a0cca4ce49fb5eb51c22a06a72020-11-25T00:03:21ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992017-12-011010.3389/fnmol.2017.00428318758DFNB1 Non-syndromic Hearing Impairment: Diversity of Mutations and Associated PhenotypesFrancisco J. del Castillo0Francisco J. del Castillo1Ignacio del Castillo2Ignacio del Castillo3Servicio de Genética, Hospital Universitario Ramón y Cajal, IRYCIS, Madrid, SpainCentro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, SpainServicio de Genética, Hospital Universitario Ramón y Cajal, IRYCIS, Madrid, SpainCentro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, SpainThe inner ear is a very complex sensory organ whose development and function depend on finely balanced interactions among diverse cell types. The many different kinds of inner ear supporting cells play the essential roles of providing physical and physiological support to sensory hair cells and of maintaining cochlear homeostasis. Appropriately enough, the gene most commonly mutated among subjects with hereditary hearing impairment (HI), GJB2, encodes the connexin-26 (Cx26) gap-junction channel protein that underlies both intercellular communication among supporting cells and homeostasis of the cochlear fluids, endolymph and perilymph. GJB2 lies at the DFNB1 locus on 13q12. The specific kind of HI associated with this locus is caused by recessively-inherited mutations that inactivate the two alleles of the GJB2 gene, either in homozygous or compound heterozygous states. We describe the many diverse classes of genetic alterations that result in DFNB1 HI, such as large deletions that either destroy the GJB2 gene or remove a regulatory element essential for GJB2 expression, point mutations that interfere with promoter function or splicing, and small insertions or deletions and nucleotide substitutions that target the GJB2 coding sequence. We focus on how these alterations disrupt GJB2 and Cx26 functions and on their different effects on cochlear development and physiology. We finally discuss the diversity of clinical features of DFNB1 HI as regards severity, age of onset, inner ear malformations and vestibular dysfunction, highlighting the areas where future research should be concentrated.http://journal.frontiersin.org/article/10.3389/fnmol.2017.00428/fullhearing impairmentinner earDFNB1GJB2connexin-26GJB6 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Francisco J. del Castillo Francisco J. del Castillo Ignacio del Castillo Ignacio del Castillo |
spellingShingle |
Francisco J. del Castillo Francisco J. del Castillo Ignacio del Castillo Ignacio del Castillo DFNB1 Non-syndromic Hearing Impairment: Diversity of Mutations and Associated Phenotypes Frontiers in Molecular Neuroscience hearing impairment inner ear DFNB1 GJB2 connexin-26 GJB6 |
author_facet |
Francisco J. del Castillo Francisco J. del Castillo Ignacio del Castillo Ignacio del Castillo |
author_sort |
Francisco J. del Castillo |
title |
DFNB1 Non-syndromic Hearing Impairment: Diversity of Mutations and Associated Phenotypes |
title_short |
DFNB1 Non-syndromic Hearing Impairment: Diversity of Mutations and Associated Phenotypes |
title_full |
DFNB1 Non-syndromic Hearing Impairment: Diversity of Mutations and Associated Phenotypes |
title_fullStr |
DFNB1 Non-syndromic Hearing Impairment: Diversity of Mutations and Associated Phenotypes |
title_full_unstemmed |
DFNB1 Non-syndromic Hearing Impairment: Diversity of Mutations and Associated Phenotypes |
title_sort |
dfnb1 non-syndromic hearing impairment: diversity of mutations and associated phenotypes |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Molecular Neuroscience |
issn |
1662-5099 |
publishDate |
2017-12-01 |
description |
The inner ear is a very complex sensory organ whose development and function depend on finely balanced interactions among diverse cell types. The many different kinds of inner ear supporting cells play the essential roles of providing physical and physiological support to sensory hair cells and of maintaining cochlear homeostasis. Appropriately enough, the gene most commonly mutated among subjects with hereditary hearing impairment (HI), GJB2, encodes the connexin-26 (Cx26) gap-junction channel protein that underlies both intercellular communication among supporting cells and homeostasis of the cochlear fluids, endolymph and perilymph. GJB2 lies at the DFNB1 locus on 13q12. The specific kind of HI associated with this locus is caused by recessively-inherited mutations that inactivate the two alleles of the GJB2 gene, either in homozygous or compound heterozygous states. We describe the many diverse classes of genetic alterations that result in DFNB1 HI, such as large deletions that either destroy the GJB2 gene or remove a regulatory element essential for GJB2 expression, point mutations that interfere with promoter function or splicing, and small insertions or deletions and nucleotide substitutions that target the GJB2 coding sequence. We focus on how these alterations disrupt GJB2 and Cx26 functions and on their different effects on cochlear development and physiology. We finally discuss the diversity of clinical features of DFNB1 HI as regards severity, age of onset, inner ear malformations and vestibular dysfunction, highlighting the areas where future research should be concentrated. |
topic |
hearing impairment inner ear DFNB1 GJB2 connexin-26 GJB6 |
url |
http://journal.frontiersin.org/article/10.3389/fnmol.2017.00428/full |
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