Portuguese Version

Year:  2003  Vol. 69   Ed. 1 - (15º)

Artigo Original

Pages: 100 to 104

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Genetic hearing loss

Author(s): Ricardo Godinho,
Ivan Keogh1,
Roland Eavey1

Keywords: genetics, hearing loss, connexin 26, counseling.

Abstract:
Introduction: The progress in research of genetic hearing loss has advanced our understanding of the molecular mechanisms that govern inner ear development, function and response to injury and aging. In the developed world, over 50% of childhood deafness is attributable to genetic causes and even age related hearing loss has been associated with genetic mechanisms. Objective: The objective of this review is to summarize recent knowledge in genetic hearing loss. Material and Method: The literature review included articles indexed at MEDLINE (The National Library of Medicine, The National Institute of Health - USA) focusing on publications from the last 3 years plus the information available at Hereditary Hearing Loss Home Page. Conclusion: Advances in the genetics of hearing loss have enhanced our comprehension of auditory function and have made possible more accurate diagnosis. Hopefully, as we further understand the molecular elements of the auditory system, this knowledge will help in the development of new therapies for the treatment of the underlying genetic defects.

INTRODUCTION

The publication of the human genome sequence in February 2001 is a clear example of the fantastic scientific progress of the last century1. Upon the elucidation of the genetic code, our capacity of understanding the nature and content of the genetic information lead us to a new millenium of Molecular Genetics. In the final stages of the Human Genome project, the 3 billion pairs of genome base were being sequenced at a speed of 1,000 pairs of base per second1. There are approximately 30,000 genes in the human genome and even though it seems to be a small number, each gene has the potential to codify up to 3 proteins. This process, known as gene alternative splicing, generates a diversity of protein products known as human proteoma.

Hearing loss is the most common sensorial deficit and results in restriction of spoken language skills. One in each thousand children is born deaf or becomes profoundly or severely deaf before language is acquired (pre-lingual period)2. Other 2 or 4 children in each 1,000 will become deaf or have some kind of hearing loss when they reach the adult life2. In developed countries, over 50% of deafness cases in childhood are attributed to genetic causes2. Up to the 7th decade, over 60% of the population will have a hearing loss greater than 25dB3.

Despite the fact that age-related hearing loss is associated with multiple factors, only recent did investigators started to understand the hereditary nature of presbycusis.

LITERATURE REVIEW

History of the Genetic Hearing Loss

For various centuries, some doctors had observed that deafness of congenital origin in children could be detected in siblings. However, the research studies related causes of hearing loss and deafness or congenital origin only after the second half of the 19th century.

In 1853, in Dublin, Sir William Wilde conducted the first systematic study related to congenital deafness. He reported the hereditary etiology of congenital deafness and observed that parental consanguinity increased the chances of the pathology4. In 1858, the German ophthalmologist Albrecht von Graefe described the occurrence of retinitis pigmentosa and congenital deafness in three brothers. Mendel's Laws, published for the first time in 1865, were not appreciated as an explanation for the hereditary transmission of the disease up to the 20th century. In 1914, Charles Usher, in Aberdeen, described the transmission of congenital deafness and retinitis pigmentosa in various families and identified them as hereditary conditions.

In 1992, the first gene responsible for DFNAI (autosomal dominant nonsyndromic deafness) was mapped in the chromosome 5 by Leon et al.6. Since then, more than 20 genes were identified as involved in nonsyndromic hearing loss. An even larger number of genes related to syndromic hearing loss have been reported and over 400 genetic syndromes have been associated with hearing loss and are listed in the OMIN web site (Online Mendelian Inherited in Man)7.

Classification

When congenital hearing loss is an associated symptom it is known as nonsyndromic hearing loss (NSHL). When hearing loss is associated with other symptoms, it is known as syndromic hearing loss (SHL). NSHL are responsible for approximately 70% of all genetic hearing losses. The genetic hearing loss is predominantly monogenic and presents high heterogeneity, with an estimated number of 50 to 100 genes involved8.

Congenital hearing losses can be transmitted by means of autosomal dominant patterns (15%), autosomal recessive pattern (80%), sex-linked (2-3%) and mitochondrial pattern (1-2%).
The complete list of loci and genes related to different types of genetic hearing loss are found in the internet at the Hereditary Hearing Loss Home page9.

Genetic Nonsyndromic Hearing Loss

Genetic nonsyndromic hearing losses are classified as autosomal dominant and autosomal recessive and they are internationally known as DFNA and DFNB, respectively.

There are at least 41 loci related to genetic hearing losses of dominant pattern (DFNA 1-41) and 30 of recessive pattern (DFNB 1-30) that are listed in the Hereditary Hearing Loss Home page9. The phenotype of DFNB is characterized as severe or profound pre-lingual auditory loss, whereas DFNA is usually post-lingual and progressive. The genes involved in NSHL codify a variety of proteins, such as: ion channels, extracellular matrix components and proteins of the essential synaptic vesicles for the traffic of inter-cellular information2, 8.

Autosomal Dominant Genetic Nonsyndromic Hearing Loss - DFNA

Almost all genes related to DFNA are characterized by post-lingual hearing loss and progressive characteristics. With few exceptions, DFNA starts as of the 2nd and 3rd decades of life, enabling normal language development2. In 1992, the first gene related to DFNA (DFNA-1) was located in chromosome 54 by Leon et al.6. The gene HDIA1 is a member of the formin family and is involved in cytokinesis and cell polarity.

Gene GJB3 codifies connexin 31 and is abnormal in DFNA-2. Connexin 26 (Cx26) is involved in DFNA-3. In 1996, DFNA-9 was mapped in the chromosome 14 and next researchers discovered the mutation responsible for the hearing loss in gene COCH, which is expressed in the cochlear and vestibular tissues10. This is the only dominant locus associated with vestibular problems and genetic family studies have suggested a possible role for the gene COCH in Meniere's disease.

Autosomal Recessive Genetic Nonsyndromic Hearing Loss - DFNB

In 1994, Guilford et al. discovered the first gene locus related to DFNB (DFNB-1) in chromosome 13 in the region of q12-1310. The importance of this discovery was soon apparent. Within this region in chromosome 13, the gene GJB2 codifies the protein Cx26. Cx26 is a member of the gap-junction protein family related to potassium transport. High concentrations of intracellular potassium is an essential component for auditory physiology8. Cx26 is considerably expressed in the cochlea, especially in the region of non-sensorial cells of Corti's organ. Mutations of this gene have been described as responsible for over 50% of the cases of NSHL and for 20% of all pre-lingual hearing losses in developed countries. A simple mutation predominates, 35delG, with a frequency in the general population of 2 to 4%9. Therefore, the incidence of this mutation of Cx26 in the general population is similar to that found in cystic fibrosis7, 9. These findings have attracted a growing interest related to screening of 35delG mutation in Cx26 as a cause of congenital deafness and the test is now commercially available in Brazil.

Since 1994, a growing number of other interesting gene mutations have been discovered. Mutations of gene MYO7A, located in chromosome 11, are responsible for DFNB-2. Gene MYO7A is a non-conventional myosin with restricted expression in stereocilia of Corti's organ11. This structural protein is responsible for the formation of bridges between the center of the actin molecule that composes the stereocilia and its extracellular connections. Mutations of this gene are also responsible for Usher syndrome type 1B and DFNA11. Mutations in myosin 15 cause DFNB3 and TECTA gene, related to the tectorial membrane, is abnormal in DFNA218. All genes associated with this type of hearing loss are listed in the Hereditary Hearing Loss Home Page.

Syndromic Genetic Hearing Loss

About 30% of the genetic hearing losses are associated with a syndrome and there are about 400 syndromes associated with hearing loss . Frequently, hearing loss in syndromic children can be conductive, mixed or sensorineural. Embryological malformations of the ear are also present.

Usher, Pendred, Jervell and Lange-Nielsen Syndromes and others also present gene mutations related to NSHL. Pendred syndrome is an autosomal recessive disease characterized by sensorineural hearing loss and thyroid dysfunction12, 13. Thyroid dysfunction is not present at birth and can develop at the beginning of the puberty of adult age. The hearing loss is associated with a widened vestibular aqueduct, which can be demonstrated radiologically. PDS gene, responsible for the syndrome, codified the protein carrier of potassium that is also related to DFNB4.

The gene responsible for Bjonstad syndrome (congenital hearing loss and pili torti) was mapped in chromosome 2 by a team of researchers that included a Brazilian Otorhinolaryngologist14.

Usher syndrome has been related to mutations in at least 11 different loci15. There are three clinical forms: Type I - profound hearing loss and vestibular abnormalities; Type II - hearing loss with no vestibular abnormalities; Type III - progressive hearing loss and variable vestibular pathology. This autosomal recessive and highly heterogeneous syndrome is caused by deafness followed by blindness and it is recognized as the most severe form of sensorial deficit4, 5, 16.

Waardenburg syndrome (hearing loss + tegument abnormality) presents 4 clinical presentations (Type I - with dysthopia canthorum, Type II: without dysthopia canthorum, Type III: upper limb malformation + Type I; Type IV: Hirschprung disease + Type III). Molecular classification shows at least 5 categories caused by 3 different genes7, 16.

Investigations about the syndromes of Usher and Waardenburg have demonstrated that the syndromes present a spectrum of diseases. The understanding of the effect related to molecular genetics of these diseases and how they overlap with the mutations caused by NSHL will promote the onset of new therapeutic possibilities.

Sex-linked hearing loss

Mutations of chromosome X that cause hearing loss are approximately 2% of all hereditary hearing loss. Internationally, these hearing losses are known as DFN 8, 9, 16. Different clinical conditions, syndromic or not, have been associated with sex-linked heredity. Hearing loss can be congenital, progressive sensorineural, high frequency sensorineural, conductive, sensorineural or mixed.

X-linked hearing loss amounts to 85% of all the cases of Alport Syndrome8, 16. This syndrome is characterized by progressive sensorineural hearing loss in various intensities associated with progressive glomerunephritis and varied ophthalmologic findings.

Mutations of gene DDP (deafness dystonia peptide) of DFN1 are related to hearing loss, abnormalities of visual acuity, dystonia, fractures and mental retardation8, 9, 17.

Nonsyndromic hearing loss DFN2 and DFN4 present profound hearing loss8, 16, 17. Mutations of gene of transcription factor POU3F4 in locus DFN3 causes mixed hearing loss and it is associated with perilymphatic fistula during the stapedial surgery. Therefore, surgeries to correct the fixation of the stapedial should be assessed concerning the possibility of abnormal communication between the cerebrospinal fluid and the perilymph 7, 8, 16. DFN6 is characterized by bilateral high frequency hearing loss that starts at the age of 5-7 years and progresses to severe/profound hearing loss, reaching all frequencies8, 16, 17. The genes located in loci DFN5, DFN7 and DFN8 have not been reported yet9.

Mitochondrial hearing loss

Mitochondria has its own molecule of DNA (mtDNA), arranged circularly, and it is responsible for the codification of 37 genes18. These genes are involved in the complex process of oxidative phosphorilation and ATP production. Mitochondrial DNA is inherited exclusively from the mother and has a rate of mutation ten times greater than the genomic DNA. The organs and tissues that need high energy supply, such as nerves and muscles, are the most affected ones by the mutations of mitochondrial DNA. It also explains the affection of hearing as a consequence of mitochondrial diseases. The association of diabetes mellitus and hearing loss has been related as a mitochondrial mutation of A3243G.19 The hearing loss does not manifest until the subject developed diabetes. It is also highly probable that mitochondrial mutations are related to presbycusis. Patients with presbycusis showed a high number of mutations of mtDNA in auditory tissues, such as for example, mutations of genes 12S Rrna e Trna (ser)UCN.18,19

The main clinical application of mitochondrial mutations is the prevention of hearing loss caused by aminoglycoside. Hu et al. in 1991 reported that 21.9% of the population of mute people in the district of Shanghai had hearing loss induced by aminoglycosides 14. This is a significant and preventable cause of hearing loss and it is due to mutation A1555G of gene 12S rRna16. This mutation makes the mtDNA more similar to bacterial DNA, and therefore, more susceptible to the action of antibiotics18. The physicians can investigate the history of aminoglycoside-induced hearing loss before the administration of these antibiotics and consider the screening for mutation A1555G in patients that should use aminoglycoside. This genetic test is now commercially available in Brazil.

The diagnosis of these problems is important for genetic counseling and screening for mutations of A1555G is indicated in all families that present a hearing loss pattern compatible with maternal transmission.

Genetic Counseling

Genetic diseases are a significant cause of morbidity and mortality. Genetic counseling is the process through which information and support is given to the patient with hearing loss and the family of people with congenital abnormalities or genetic diseases. Genetic counseling is also directed to high risk subjects to have genetic diseases17. Sessions of genetic counseling normally last one hour or more, depending on the case complexity.

Genetic tests are an option for subjects and families with deafness. It is known that 95% of the deaf children born of parents with no hearing affection and 31% of the sporadic deafness etiology are caused by mutations of Cx26. Therefore, it is important to provide to parents the genetic tests and the information related to pre-natal diagnosis, diagnosis of mutations, status of carrier and chances of recurrence20.

A good example of the clinical application related to the identification of those with a mutation related to hearing loss is the fact that 20% of all newborns with deafness will be positive in the genetic test for mutations of connexin 26 gene and these children have excellent prognosis for cochlear implant and language development early interventions8, 21, 22. However, detection of Cx26 mutation does not necessarily indicate the involvement of the gene in the etiology of deafness: some deaf patients present mutation of 35delG in only one allele and some cases present mutations that are not necessarily pathological21, 23. Therefore, otorhinolaryngologists that follow up deaf children should be attentive to the possibilities and careful when counseling the families.

Mutations in the gene related to Pendred syndrome can be screened when the radiological abnormalities of the temporal bone follow the cases of hearing loss8. This type of lab screening is not available in Brazil yet.

Molecular genetic lab tests are available in some countries for the diagnosis of brachi-oto-renal syndrome and Stickler syndrome. Tests for Usher and Waardenburg syndromes are available for research purposes only.

Some authors recommended that all family members of patients who developed aminoglycoside-related ototoxicity should be tested for mitochondrial mutation A1555G.23

Universal screening for hearing loss is impractical right now owing to the large size of some genes and to the little significant contribution from an epidemiological perspective of various deafness genes. However, the precise genetic diagnosis is important for the correct definition of treatment and genetic counseling. Currently, genetic test is clinically available in Brazil for a limited number of genes, but this situation will be different in the near future as the studies in this area progress and lab gene screenings become more effective.

CLOSING REMARKS

The hearing system is an integral part of the communication system of human beings. In society, aural communication is predominant and any subject with hearing loss can become isolated. The evolution caused by molecular genetics has caused an enormous impact in the study of hearing and its diseases. These advances will provide more accurate diagnosis, early intervention and better results. As we understand the genetic and molecular fundamentals of the hearing system, this knowledge will help the development of new therapies and even the repair of the genetic defect.

ACKNOWLEDGEMENTS

IJK would like to acknowledge The Royal College of Surgeons in Ireland for a surgical traveling fellowship in 2001.

REFERENCES

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1 Department of Otolaryngology, Massachusetts Eye and Ear Infirmary. Department of Otology and Laryngology, Harvard Medical School, Boston MA USA.
2 Institute of Biological Sciences and Health, PUC-MINAS, Belo Horizonte MG/Brazil. Centro Mineiro de
Otorrinolaringologia Pediátrica, Belo Horizonte MG/Brazil

Address correspondence to: Ricardo Neves Godinho - Rua Joaquim Coura 347 - Cemig Sete Lagoas MG 35700-149 Brazil - Tel/fax: (55 31) 3776-3236 - E-mail: ricardongodinho@netscape.net

Financial support - CAPES -Brasilia

Article submitted on August 13, 2002. Article accepted on October 17, 2002.

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