Nuclear and mitochondrial genes mutated in nonsyndromic impaired hearing

doi:10.1016/j.ijporl.2004.12.002

International Journal of Pediatric Otorhinolaryngology

Volume 69, Issue 5, May 2005, Pages 621-647

https://doi.org/10.1016/j.ijporl.2004.12.002 Get rights and content

Summary

Half of the cases with congenital impaired hearing are hereditary (HIH). HIH may occur as part of a multisystem disease (syndromic HIH) or as disorder restricted to the ear and vestibular system (nonsyndromic HIH). Since nonsyndromic HIH is almost exclusively caused by cochlear defects, affected patients suffer from sensorineural hearing loss. One percent of the total human genes, i.e. 300–500, are estimated to cause syndromic and nonsyndromic HIH. Of these, approximately 120 genes have been cloned thus far, approximately 80 for syndromic HIH and 42 for nonsyndromic HIH. In the majority of the cases, HIH manifests before (prelingual), and rarely after (postlingual) development of speech. Prelingual, nonsyndromic HIH follows an autosomal recessive trait (75–80%), an autosomal dominant trait (10–20%), an X-chromosomal, recessive trait (1–5%), or is maternally inherited (0–20%). Postlingual nonsyndromic HIH usually follows an autosomal dominant trait. Of the 41 mutated genes that cause nonsyndromic HIH, 15 cause autosomal dominant HIH, 15 autosomal recessive HIH, 6 both autosomal dominant and recessive HIH, 2 X-linked HIH, and 3 maternally inherited HIH. Mutations in a single gene may not only cause autosomal dominant, nonsyndromic HIH, but also autosomal recessive, nonsyndromic HIH (GJB2, GJB6, MYO6, MYO7A, TECTA, TMC1), and even syndromic HIH (CDH23, COL11A2, DPP1, DSPP, GJB2, GJB3, GJB6, MYO7A, MYH9, PCDH15, POU3F4, SLC26A4, USH1C, WFS1). Different mutations in the same gene may cause variable phenotypes within a family and between families. Most cases of recessive HIH result from mutations in a single locus, but an increasing number of disorders is recognized, in which mutations in two different genes (GJB2/GJB6, TECTA/KCNQ4), or two different mutations in a single allele (GJB2) are involved. This overview focuses on recent advances in the genetic background of nonsyndromic HIH.

Introduction

Impaired hearing is the most common sensory disorder worldwide [1]. Approximately 70 million patients worldwide suffer from impaired hearing, resulting in disturbed communication [2]. In 50–60% of them, impaired hearing is due to a genetic cause (hereditary impaired hearing, HIH) and in 40–50% of the cases acquired due to prematurity, neonatal hypoxia, pre or postnatal infections, ototoxic drugs, or acoustic or cranial trauma [1], [2]. Concerning congenital HIH, 1 in 1000 life births is affected and the incidence of genetic causes is at least 1:2000 [2], [3], [4]. In the United States, the rate of bilateral HIH > 35 dB is 1.4–3/1000 [5], [6] and in Europe 1.4–2.1/1000 [7], [8], [9]. The relative incidence of congenital HIH is increasing, since acquired impaired hearing from meningitis is decreasing as a consequence of antibiotic therapy and vaccination programs [10]. Principally, HIH may be due to affection of the external acoustic canal, the middle ear, the internal auditory canal, the inner ear, the acoustic nerve, or the brain (Table 1). Additionally, HIH may be part of a multisystem syndrome (syndromic HIH) or occur isolated (nonsyndromic HIH).

This review focuses on the advances in the identification of genetic causes of nonsyndromic HIH. Because of the high number of syndromes associated with HIH, only those are mentioned, which are allelic to nonsyndromic HIH. Since nonsyndromic HIH is almost exclusively caused by cochlear defects [11], this paper mainly deals with sensorineural hearing loss (SNHL). It also references Web addresses dealing with the topic [12].

Section snippets

History

Localization and identification of genes for HIH started in the early 90s [2]. The first locus mapped was that of DFNA1 in a large Costa Rican family with autosomal dominant, nonsyndromic HIH [1]. In 1992, mutations in the PAX3 gene were detected, which caused Wardenburg syndrome [2]. Subsequently, it was discovered that Wardenburg syndrome is genetically heterogeneous [2]. The first genetic defect causing nonsyndromic HIH was discovered in 1993 and was a mitochondrial mutation [13]. In 1994,

Anatomy and physiology of hearing

In response to sound waves, movement of the tympanic membrane is amplified by the ossicular chain of the middle ear to generate compression waves in the perilymph-filled scala vestibuli. The wave moves the tectorial membrane, built up of various collagens and tectorin, in the cochlear duct and produces a shearing motion, which bends the triplet of hairs (stereocilia) of the single row of inner and the three rows of outer hair cells of Corti's organ. The stereocilia tips of the outer hair cells

Classification of HIH

HIH can be classified according to various criteria, listed in Table 1. Most frequently, HIH is classified as syndromic or nonsyndromic, or according to its transmission via an autosomal dominant (Table 2), autosomal recessive (Table 3), X-chromosomal recessive (Table 3), or maternal trait [10]. X-chromosomal dominant and Y-linked transmission are rare. Another useful classification divides HIH according to its onset before (prelingual) or after acquisition of speech (postlingual). As a rule of

Epidemiology and frequency

Generally, 50–80% of the cases with congenital, prelingual HIH occur as the only trait (nonsyndromic) [10], [11], [18]. Prelingual HIH is transmitted via an autosomal recessive trait (75–80%), an autosomal dominant trait (10–20%), is X-linked (1–5%), or maternally inherited (0–20%), depending on the investigated population [2], [10], [11]. Concerning the frequency of postlingual SNHL, many families have been described, but no systematic epidemiologic studies have been carried out. Nonsyndromic

General remarks

Of the 30,000–50,000 human genes, 1%, i.e. 300–500 genes, are estimated to be necessary for hearing [4]. Accordingly, HIH has been identified as part of the clinical presentation in more than 300 genetic syndromes. Today, approximately 120 independent genes for HIH, approximately 80 for syndromic and 41 for nonsyndromic HIH, have been identified, which is about one-third of the total [19]. Of the 41 mutated genes, which cause nonsyndromic HIH, 15 cause autosomal dominant HIH, 15 autosomal

General remarks

The first genetic defect causing nonsyndromic SNHL was detected in 1993 and was a mitochondrial mutation [13]. Various mtDNA mutations, causing progressive, nonsyndromic, symmetric bilateral HIH, have been identified since then. MtDNA mutations associated with HIH frequently occur in the 12S-rRNA or in tRNA genes. Mutations in the 12S-rRNA account for most of the cases with aminoglycoside-induced oto-toxicity (Table 7) [20]. Another hot spot for nonsyndromic, maternally inherited impaired

Diagnostic procedure

To properly classify nonsyndromic HIH, it is important to fully examine every individual. The diagnostic procedure should start with a carefully taken history, including an extensive family history. A pedigree of at least three generations should be constructed. After thorough physical examination with particular regard to audiologic and vestibular functions, instrumental investigations should follow (Table 8). After having excluded syndromic HIH, by appropriate investigations, all patients

Genetic counseling

For optimal counseling strategies it is required to understand the attitudes of the normally hearing parents (90–95% of the cases) of deaf children. The majority of these parents approves genetic testing and believes that it should be offered prenatally [167]. The vast majority of these parents, however, has inaccurate beliefs about their own and children's recurrence risk, irrespective of whether they had undergone genetic testing or not. One-third of these patients believe that the absence of

Conclusions

Since recent years the molecular genetic background of nonsyndromic HIH is rapidly increasing. Accordingly, genetic testing of nonsyndromic HIH patients is now used for diagnostic purposes, and has been integrated in the decision for treatment, genetic counseling, and management. Despite these recent advances in the clarification of nonsyndromic SNHL by molecular genetic techniques, ethical concerns about its application should be considered. Sensitive genetic counseling, performed by a skilled

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T8M mutation in connexin-26 impairs the connexon topology and shifts its interaction paradigm with lipid bilayer leading to non-syndromic hearing loss
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Citation Excerpt :
Inability of gap-junction proteins to transport IP3 across lipid bilayer reduces Ca2 + signaling in the supporting cells which may influence the Ca2 +-dependent K+/Cl− balance of cochlear fluids, leading to HL [6]. Approximately, 50% of sensorineural deafness is caused by the mutations in Connexin (Cx) family members [7]. The heterologous Cxs are transmembrane proteins that assemble heteromeric or homomeric hemichannels (homogeneous connexons) by oligomerizing them in hexameric fashion [8].
Approximately, two third cases of non-syndromic deafness are caused by mutation in GJB2; which encodes a β-class gap-junction protein, connexin-26 (Cx26). Cx26 is expressed in cochlea, inner ear and epidermis. It plays an important role in the process of sound transduction through cochlea by permitting the distribution of ions and second messengers (cAMP and inositol 1,4,5-triphosphate (IP3)) through adjacent cells. Any damage in Cx26 structure may disturb the equilibrium of auditory cells and underlying auditory neurotransmission of ions through cochlea which results in partial or complete hearing loss. Current study establishes the use of in-silico approaches to characterize a known deafness-associated frameshift mutation (T8M) in Cx26. The Ca^2 + ion interactions were comparatively evaluated in Cx26^WT and Cx26^T8M structures. Clearly, more stable interactions of Cx26^WT were observed with Ca^2 + as compared to Cx26^T8M, indicating significant changes in the connexon-membrane topology of Cx26^T8M. We observed noteworthy differences in Cx26^T8M-based tunnel formation and pore characteristics as well as structural differences which may affect release of Ca^2 + ions. Thus disturbance in ionic concentration may dysfunction the cochlear hair cells leading to non-syndromic deafness.
Prevalence and audiological profiles of GJB2 mutations in a large collective of hearing impaired patients
2016, Hearing Research
Mutations in the GJB2 gene are known to represent the commonest cause of hereditary and congenital hearing loss. In this study, a complete sequencing of the GJB2 gene in a cohort of 506 patients from a single, large cochlear implant program in Europe was performed. Audiological testing for those patients who could actively participate was performed using pure tone audiometry (PTA). Those unable to undergo PTA were measured using click-auditory brainstem response (ABR). Data analysis was performed to determine genotype–phenotype correlations of the mutational status vs. audiological profiles and vs. age at the time of presentation. An overall prevalence of biallelic mutations of 13.4% was found for the total collective. When subsets of younger patients were examined, the prevalence increased to 27% of those up to age 18 and 35% of those up to age 5 at the time of testing, respectively. This increase was found to be highly significant (p < 0.001). Analysis of the mean PTA thresholds revealed a strong correlation between allele combination status and mean PTA (p = 0.021). The prevalence of simple heterozygotes was found to be approximately 10.1%, which is around 3.3 times the value expected in the general population. As GJB2 follows a recessive pattern of inheritance, the question arises as to why such a large fraction of simple heterozygotes was observed among the hearing impaired patients included in this study.
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Citation Excerpt :
Current research estimates that 1% of the 30,000—50,000 human genes are necessary for hearing, of which more than 95 independent genes and 170 loci have been identified as causes of HL [8–10]. The majority of deaf children are born to normal hearing parents (90–95%) and in most of these families there is no history of HL [7,8,11,12]. It is caused by the fact that the autosomal-recessive forms of HL are most common and usually more severe than the other forms of sensorineural hearing loss (SNHL) [13].
The present study was initiated to establish the etiological causes of early onset hearing loss (HL) among Estonian children between 2000–2009.
The study group consisted of 233 probands who were first tested with an arrayed primer extension assay, which covers 199 mutations in 7 genes (GJB2, GJB6, GJB3, SLC26A4, SLC26A5 genes, and two mitochondrial genes – 12S rRNA, tRNA^Ser(UCN)). From probands whose etiology of HL remained unknown, DNA analysis of congenital cytomegalovirus (CMV) infection and G-banded karyotype and/or chromosomal microarray analysis (CMA) were performed.
In 110 (47%) cases, the etiology of HL was genetic and in 5 (2%) congenital CMV infection was diagnosed. We found mutations with clinical significance in GJB2 (100 children, 43%) and in 2 mitochondrial genes (2 patients, 1%). A single mutation in SLC26A4 gene was detected in 5 probands (2.2%) and was considered diagnostic. In 4 probands a heterozygous IVS2-2A>G change in the SLC26A5 gene was found. We did not find any instances of homozygosity for this splice variant in the probands. CMA identified in 4 probands chromosomal regions with the loss of one allele. In 2 of them we were able to conclude that the found abnormalities are definitely pathogenic (12q13.3-q14.2 and 17q22-23.2 microdeletion), but the pathogenity of 2 other findings (3p26.2 and 1p33 microdeletion) remained unknown.
This practical diagnostic algorithm confirmed the etiology of early onset HL for 115 Estonian patients (49%). This algorithm may be generalized to other populations for clinical application.
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2012, International Journal of Pediatric Otorhinolaryngology
Mutations in OTOF have been reported to cause nonsyndromic hearing loss in different populations. The purpose of this study is screening of OTOF mutations in Iranian population.
Thirty-eight consanguineous families affected with autosomal recessive nonsyndromic hearing loss (ARNSHL) and negative for GJB2 or GJB6 mutations were screened by autozygosity mapping and Sanger sequencing to find OTOF mutations.
A novel homozygous frameshift mutation (c.1981dupG) was found to cause hearing loss in one family and no other OTOF variants were detected in the remaining families. The affected individuals were homozygous forp. D661GfsX2 causing defect in long isoform of otoferlin.
We conclude that OTOF mutations are not the major cause of ARNSHL in the Iranian population but still may play an important role in HL; therefore evaluation the OTOF gene is of concern.
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Nuclear and mitochondrial genes mutated in nonsyndromic impaired hearing

Summary

Introduction

Section snippets

History

Anatomy and physiology of hearing

Classification of HIH

Epidemiology and frequency

General remarks

General remarks

Diagnostic procedure

Genetic counseling

Conclusions

Lancet

Genet. Med.

Pediatr. Clin. North Am.

Genomics

Am. J. Hum. Genet.

Biochem. Biophys. Res. Commun.

Cell

J. Biol. Chem.

Hum. Genet.

J. Mol. Biol.

J. Invest. Dermatol.

Int. J. Pediatr. Otorhinolaryngol.

Lancet

Lancet

Otolaryngol. Clin. North Am.

Am. J. Hum. Genet.

Am. J. Hum. Genet.

Am. J. Hum. Genet.

Brain Res. Brain Res. Rev.

Am. J. Hum. Genet.

Am. J. Hum. Genet.

Am. J. Hum. Genet.

Hereditary deafness and phenotyping in humans

Br. Med. Bull.

Human nonsyndromic sensorineural deafness

Annu. Rev. Genomics Hum. Genet.

Universal infant hearing screening by automated auditory brainstem response measurement

Pediatrics

Molecular genetics of deafness

Otolaryngol. Clin. North Am.

Aetiology of bilateral sensorineural hearing impairment in children: a 10 year study

Arch. Dis. Child

The need for universal neonatal hearing screening—some aspects of epidemiology and identification

Acta Paediatr.

Epidemiology of genetic hearing impairment

Non-syndromic autosomal-dominant deafness

Clin. Genet.

Selected resources for hereditary hearing impairment on the world wide web

Ear Hear.

Mitochondrial deafness mutations reviewed

Hum. Mutat.

A non-syndrome form of neurosensory, recessive deafness maps to the pericentromeric region of chromosome 13q

Nat. Genet.

Connexin 26 mutations in hereditary non-syndromic sensorineural deafness

Nature

Connexin 26 mutations and nonsyndromic hearing impairment in northern Finland

Laryngoscope

Nonsyndromic deafness DFNA1 associated with mutation of a human homolog of the Drosophila gene diaphanous

Science

Insertion of beta-satellite repeats identifies a transmembrane protease causing both congenital and childhood onset autosomal recessive deafness

Nat. Genet.

The genetics of deafness

Ment. Retard. Dev. Disabil. Res. Rev.

Molecular pathogenetic mechanism of maternally inherited deafness

Ann. N. Y. Acad. Sci.

Nonsyndromic hearing loss

Ear Hear.

Genetics of deafness in India

Indian J. Pediatr.

Hereditary deafness: molecular genetics

Med. Sci. (Paris)

A mutation in the gamma actin 1 (ACTG1) gene causes autosomal dominant hearing loss (DFNA20/26)

J. Med. Genet.

Mutations in the gamma-actin gene (ACTG1) are associated with dominant progressive deafness (DFNA20/26)

Am. J. Hum. Genet.

The molecular genetics of Usher syndrome

Clin. Genet.