# 2002 Oxford University Press

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Genetics, genomics and gene discovery in the auditory system

Cynthia C. Morton*

Departments of Obstetrics, Gynecology, and Reproductive Biology and Pathology, Brigham and Womens Hospital and Harvard Medical School, Boston, MA, USA
Received April 5, 2002; Accepted April 10, 2002

The sounds of silence have forever been broken as genetics and genomics approaches in human and model organisms have provided a powerful and rapid entry into gene discovery in the auditory system. An understanding of the complexities and beauty of the biological process of hearing itself is unfolding as genes underlying hereditary hearing impairment are identied. Genes involved in modifying hearing are also being found, and will be critical to a full comprehension of genotypephenotype relationships. Investigations in the auditory system will provide important insight into how the nervous system decodes molecular information. Deafness represents a common sensory disorder that can interfere dramatically in the acquisition of speech and language in children, and in the quality of life for a growing aged population. As newborn screening for hearing impairment is being implemented in many birth hospitals, the prospects for precise clinical diagnosis, appropriate genetic counseling and proper medical management for auditory disorders has never been at a more exciting crossroad.

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INTRODUCTION
It has long been recognized that heredity plays a major role in hearing impairment. Despite the fact that understanding the genetic basis of hearing loss has fascinated human and medical geneticists for decades, only within the past few years have the genes and molecular mechanisms underlying deafness begun to be discovered. In part, this results from various obstacles to investigation of the auditory system including: inaccessibility of the sensory end organ for hearing, the cochlea, within the dense temporal bone; length of time to direct pathologic observation of the deaf ear due to an otherwise normal lifespan of individuals with hearing loss; unparalleled genetic heterogeneity; and assortative mating. The history of the genetics of deafness has had a sordid past of blatant discrimination of the deaf (1), and there is mistrust about genetics among some members of the deaf population. Nevertheless, the past few years have witnessed an explosion of discoveries that are providing fundamental insight into the biology of hearing. The frequency of hearing loss is estimated at one per thousand newborns and half of all cases are attributed to genetic causes. In addition to being a common etiology of congenital deafness, mutations in genes are responsible for progressive hearing loss, and no doubt will be found to play an important role in progressive hearing loss with ageing (presbycusis). Environmental etiologies of hearing loss are

likely to represent a declining proportion of cases as better therapies for bacterial and viral infections (e.g. vaccines) are implemented, acoustic trauma in the workplace is recognized and prevented, and ototoxic drugs (e.g. aminoglycosides) are avoided in genetically susceptible individuals.

GENETICS OF DEAFNESS
The study of the genetics of deafness is unique among inherited disorders for several reasons and illustrates well various concepts in human genetics. Notably, there is incomparable genetic heterogeneity with over 90% of matings among the deaf resulting in all hearing offspring. This reects matings among the deaf with mutations in different genes as well as matings of couples in which one individual is deaf due to a genetic mechanism and the other due to an environmental etiology. Matings among the deaf are well recognized and, with the exception of assortative mating for stature, may represent one of the most common genetic traits on which an altered mating structure occurs in human populations. Furthermore, the hearing offspring of deaf couples who themselves can be native signers are more likely than random members of the population to have a partner who is deaf due to a shared language and culture. Both genetic heterogeneity and assortative mating confound gene discovery using traditional methods of genetic linkage analysis.

*To whom correspondence should be addressed at: Department of Pathology, Brigham and Womens Hospital, 75 Francis Street, Boston, MA 02115, USA. Tel: 617 732 7980; Fax: 617 738 6996; Email: cmorton@partners.org

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Table 1. Gene discovery in the auditory system No. Gene Protein or RNA Map position Syndromic or nonsyndromic hearing loss SHL SHL NSHL SHL Disorders Reference

1 2 3

ATP6B1 BSND CDH23 barttin cadherin 23

2cenq13 1p32.3 10q21q22

4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31

CLDN14 COCH COL1A2 COL2A1 COL4A3 COL4A4 COL4A5 COL11A1 COL11A2 DDP DFNA5 DIAPH1 DSPP EDN3 EDNRB EYA1 EYA4 GJA1 GJB2 GJB3 GJB6 KCNE1 KCNQ4 KVLQT1 MITF MYH9 MYO6 MYO7A

claudin 14 cochlin collagen type collagen type collagen type collagen type collagen type collagen type collagen type

1 a2 2 a1 4 a3 4 a4 4 a5 11 a1 11 a2

21q22 14q12q13 7q22.1 12q13.1q13.2 2q36q37 2q36q37 Xq22 1p21 6p21.3 Xq22 7p15 5q31 4q21.3 20q13.2q13.3 13q22 8q13.3 6q22q23 6q21q23.2 13q12 1p34 13q12 21q22.1q22.2 1p34 11p15.5 3p12.3p14.1

NSHL NSHL SHL SHL SHL SHL SHL SHL NSHL SHL SHL NSHL NSHL SHL SHL SHL SHL NSHL NSHL NSHL NSHL NSHL SHL NSHL SHL SHL NSHL SHL NSHL NSHL SHL

diaphanous dentin sialophosphoprotein endothelin 3 endothelin receptor B

connexin 43 connexin 26 connexin 31 connexin 30

myosin heavy chain 9 myosin 6 myosin 7A

22q13 6q13 11q12.3q21

32 33 34 35

MYO15A NDP OTOF PAX3

myosin 15A norrin otoferlin

17p11.2 Xp11.3 2p22p23 2q35

NSHL SHL NSHL SHL

36 37

PCDH15 POU3F4

protocadherin 15

10q21q22 Xq21.1

SHL NSHL

Distal renal tubular acidosis associated with sensorineural deafness Bartter syndrome Usher syndrome type 1D (USH1D) Usher syndrome type 1D (USH1D) DFNB12 DFNB29 DFNA9 Osteogenesis imperfecta Stickler syndrome (STL1) Alport syndrome Alport syndrome Alport syndrome Stickler syndrome (STL2) Stickler syndrome (STL3) DFNA13 Mohr-Tranebjaerg syndrome DFNA5 DFNA1 Dentinogenesis imperfecta 1 (DGI1), DFNA39 WaardenburgShah syndrome (WS4) WaardenburgShah syndrome (WS4) Branchio-oto-renal syndrome DFNA10 Autosomal recessive deafness DFNB1 DFNA3 DFNA2 Autosomal recessive deafness DFNA3 Jervell and LangeNielsen syndrome (JLNS2) DFNA2 Jervell and Lange-Nielsen syndrome (JLNS1) Waardenburg syndrome type II (WS2) Tietz syndrome MayHegglin and Fechtner syndromes DFNA17 DFNA22 Usher syndrome type 1B (USH1B) DFNA11 DFNB2 Atypical Usher syndrome DFNB3 Norrie disease DFNB9 Waardenburg syndrome type I (WS1) Waardenburg syndrome types I III (WS1 WS3) Craniofacial dysmorphism, hand abnormalities, profound sensorineural deafness (CDHS) Usher syndrome type 1F (USH1F) DFN3

(76) (77) (10) (11) (78) (22) (79) (80) (23) (23) (20) (81) (82) (83) (16) (19) (84) (85) (86) (87) (88) (89) (67) (24) (25) (26) (90) (66) (91,92) (93) (94) (28) (95) (96) (97) (49) (7) (6) (8,9) (98) (99) (14,100) (29) (27) (101) (102)

(103,104) (105)

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Table 1. (Continued) 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 POU4F3 PMP22 12S rRNA SLC19A2 SLC26A4 SOX9 SOX10 STRC TCOF1 TECTA TMC1 TMPRSS3 tRNA-glu tRNA-leu tRNA-lys tRNA-ser tRNA-ser(UNC) transfer RNA transfer RNA transfer RNA transfer RNA transfer RNA 5q31 17p11.2 mitochondrial 1q23.3 7q31; 7q21q34 17q24.3q25.1 22q13 15q21q22 5q32q33.1 11q22q24 9q13q21 21q22.3 mitochondrial mitochondrial mitochondrial mitochondrial mitochondrial NSHL SHL NSHL SHL NSHL SHL SHL SHL NSHL SHL NSHL NSHL NSHL SHL SHL SHL SHL NSHL SHL DFNA15 CharcotMarieTooth disease Sensorineural deafness Thiamine-responsive megaloblastic anemia with diabetes mellitus and deafness Pendred syndrome (PDS) DFNB4 Campomelic dysplasia WaardenburgShah syndrome (WS4) DFNB16 Treacher Collins syndrome DFNA8, DFNA12 DFNB21 DFNA36 DFNB7/B11 DFNB8, DFNB10 Diabetes and deafness Myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) Diabetes mellitis and deafness Myoclonic epilepsy and ragged-red fiber disease (MERRF) Retinitis pigmentosum and progressive sensorineural hearing loss Sensorineural deafness Progressive myoclonic epilepsy, ataxia and hearing loss Palmoplantar keratoderma and deafness Usher syndrome type 1C (USH1C) Usher syndrome type 2A (USH2A) Usher syndrome type 3 (USH3) Wolfram syndrome DFNA6/A14 DFNA38 (69) (106) (74) (107,108) (17) (109) (110) (111) (31) (15) (21) (112) (12) (113) (114) (115) (116) (117) (118) (119) (120) (121) (30) (122) (18) (123) (124,125) (126) (127)

peripheral myelin ribosomal RNA

pendrin

stereocilin treacle alpha tectorin

55 56 57 58

USH1C USH2A USH3 WFS1

harmonin usherin wolframin

11p15.1 1q41 3q21q25 4p16

SHL SHL SHL SHL NSHL

Hundreds of syndromic forms of deafness have been described (24) and the underlying genetic mutation identied for many of the more common forms, but only 30% of genetic cases are estimated to be part of a heritable syndrome. Thus, the vast majority of genetic deafness is designated as nonsyndromic and to date over 65 loci have been mapped. Nonsyndromic hearing impairment is categorized further by mode of inheritance: approximately 77% of cases are autosomal recessive; 22% autosomal dominant; 1% X-linked; and < 1% due to mitochondrial inheritance (5). Dominant loci are designated with the prex DFNA, recessive loci DFNB, X-linked loci DFN and modifying loci with DFNM. Generally, patients with autosomal recessive hearing impairment have prelingual and congenital deafness and patients with autosomal dominant hearing impairment have postlingual and progressive hearing impairment. This observation may be explained by the complete absence of functional protein in recessive disorders, while in autosomal dominant disorders, dominant mutations may be consistent with initial function and subsequent hearing impairment due to a cumulative, degenerative process. A recent tally of nonsyndromic hearing loss disorders reveals 32 autosomal dominant, 27 autosomal recessive, and 4 X-linked forms (4). It remains to be shown whether each of these loci will correspond to a unique gene. In fact, various deafness disorders have been found already to be

the result of the same genetic etiology (e.g. DFNA8 and A12; DFNA6, A14 and A38). In addition, at least 58 auditory genes have been identied: 16 for autosomal dominant and 11 for autosomal recessive loci, and 1 for an X-linked locus; 6 mitochondrial genes and at least 38 genes for syndromic hearing loss have also been discovered (n.b. some genes cause multiple forms of deafness) (Table 1). Although this magnitude of progress is remarkable and signicant advances have been made, it is clear that many more genes for hearing await detection. Mutations within the same gene have been found to result in a variety of clinical phenotypes with different modes of inheritance. For example, mutations in MYO7A are pathogenetic in the autosomal recessive deafness and blindness disorder Usher syndrome type 1B (USH1B), and in two nonsyndromic hearing disorders, DFNB2 and DFNA11, displaying autosomal recessive and dominant segregation, respectively. It has been suggested that the mutation in DFNA11, a 9 bp deletion in the coiled-coil domain of MYO7A which is involved in dimerization, could have a dominant negative effect (6) as compared to splicing and missense mutations observed in recessive USH1B and DFNB2 (79). Another example of phenotypic heterogeneity also involving Usher syndrome is seen in mutations in CDH23 detected in USH1D and DFNB12 (10,11). Mutations in PDS cause Pendred syndrome and nonsyndromic autosomal recessive

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hearing loss, DFNB4. Similarly, mutations in WFS1 cause Wolfram syndrome and also account for an autosomal dominant nonsyndromic deafness, DFNA6/A14/A38. Most recently, DFNA36 and DFNB7/B11 were determined to be the result of mutations in TMC1 (12).

Organ and tissue-specic methods for auditory candidate genes A complementary method to genetic linkage analysis for gene identication is one that utilizes tissue or organ-specic cDNA libraries to provide candidate genes (3234). A transcript map of the inner ear provides a ready source of positional candidate genes for mutation screens in gene discovery efforts. To this end, cochlear cDNA libraries constructed from human (35,36) and mouse (37) have provided precious biological tools for gene discovery in the mammalian cochlea. A cDNA library from an analogous organ in chicken, the basilar papillae, has also been of great value (38). Almost 15 000 human (Morton fetal cochlear cDNA library) and 1600 mouse (Soares mouse NMIE cDNA library) inner ear ESTs are currently available in GenBank and the sequences of an additional 9000 mouse ESTs will soon be deposited there. ESTs derived from two sequencing projects from human cochlear cDNA clones (39,40) have elucidated thousands of potential positional candidate genes for hearing disorders (41) in addition to providing a snapshot of gene expression in the 1622 week gestational age fetal cochlea. BLAST analysis of 8153 human ESTs revealed that about 50% (n 4040) had sequence similarity to a total of 1449 known human genes. The most abundantly expressed gene was COL1A2, and two other collagens, COL3A1 and COL1A1, were among the most highly represented transcripts. In total, 10 different collagen genes were present in the cochlear ESTs. Forty-three human homologs of nonhuman mammalian genes were also identied, and among them are ESTs for membrane proteins, extracellular proteins and trafcking proteins. Of the remaining 4055 ESTs,

GENOMIC APPROACHES TO GENE DISCOVERY IN THE AUDITORY SYSTEM

Traditional methods for mapping disease genes, such as genetic linkage analysis, have a less than totally optimal use in gene discovery efforts for hearing disorders, mainly because of the complex genetic nature of deafness. Successful use of genetic linkage for mapping hearing disorders, especially for autosomal recessive nonsyndromic loci, has been restricted largely to consanguineous kindreds or populations in which there has been limited immigration. Even in families in which a heritable hearing disorder is successfully mapped, there is often an insufcient number of recombination events to narrow a chromosomal interval, resulting in a candidate region consisting of megabases of genomic DNA. Positional cloning has been productive for a modest number of human deafness genes including NDP (13,14), TCOF1 (15), DDP (16), SLC26A4 (17), USH2A (18) and DFNA5 (19). Positional candidate genes from human (e.g. COL4A5 (20), TECTA (21), COCH (22), COL4A and 4A4 (23), GJB2 (24,25), GJB3 (26)) and mouse (e.g. PAX3 (27), MITF (28), OTOF (29), USH1C (30), STRC (31)) among others have been the primary method for gene identication.

Table 2. Web resources for genetic and genomic studies of the auditory system Web page name Connexin-deafness homepage Corey lab Harvard Medical School Center for Hereditary Deafness Hereditary hearing impairment in mice Hereditary hearing loss homepage Morton hearing research group MRC Institute of Hearing Research inner ear mutant table MRC Institute of Hearing Research inner ear developmental gene expression table National Institute on Deafness and Other Communication Disorders OMIM Otobase Tour de loreille, Universite Montpellier Univ. of WI Dept. of NeurophysiologyHearing and Balance Washington Univ. inner ear protein database Summary of contents Information on connexin mutations Microarray expression data from mouse inner ear Resources for families, clinicians and researchers Results from a large scale mouse screening program Syndromic and nonsyndromic disorders, mitochondrial disorders, otosclerosis Human cochlear ESTs summary and map locations Mouse mutants with various inner ear defects Developmental gene expression in the inner ear in a variety of species Research from the Laboratory of Molecular Genetics and other resources Human heritable disorders Repository of candidate genes for inner ear disorders in human, mouse and zebrafish Anatomy, physiology and pathophysiology of the auditory system Educational and research resources Catalog of biochemical characterization of tissues and fluids of the inner ear URL www.iro.es/deafness/ www.mgh.harvard.edu/depts/ coreylab/index.html hearing.harvard.edu www.jax.org/research/hhim www.uia.ac.be/dnalab/hhh/ hearing.bwh.harvard.edu www.ihr.mrc.ac.uk/hereditary/ MutantsTable.shtml www.ihr.mrc.ac.uk/hereditary/ genetable/index.shtml www.nidcd.nih.gov/ www.ncbi.nlm.nih.gov/entrez/ query.fcgi?db OMIM Hudspeth-sgi.rockefeller.edu www.iurc.montp.inserm.fr/cric/ audition/english/start.htm www.neurophys.wisc.edu/h%26b oto.wustl.edu/thc/innerear2d.htm

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Table 3. Mouse hearing loss mutants and their human homologs Mouse mutant Ames waltzer (av) Beethoven (Bth) and deafness (dn) chondrodysplasia(cho) Col1a1 transgene disruption Col11a2 targeted null Col4a3 targeted null Disproportionate micromelia (Dmm) and mutant transgenes Dominant megacolon (Dom) dominant spotting (W) Eya1bor and targeted null Fgfr3 targeted null Gata targeted null Kcne1 targeted null and Kcne1pkr Kcnq1 targeted null lethal spotting (ls) microphthalmia (mi) Ndph targeted null Pax2 targeted null piebald (s) Pou3f4 targeted null and sex-linked fidget (slf) Pou4f3 targeted null and dreidel (ddl) quivering (qv) shaker-1 (sh1) shaker-2 (sh2) Slc26a4 targeted null Snells waltzer (sv) splotch (Sp) Tecta targeted null Thrd targeted null tremble (Tr) waltzer (v) Gene Pcdh15 Tmc1 Col11a1 Col1a1 Col11a2 Col4a3 Col2a1 Sox10 Kit Eya1 Fgfr3 Gata3 Kcne1 Kcnq1 Edn3 Mitf Ndph Pax2 Ednrb Pou3f4 Pou4f3 Spnb4 Myo7a Myo15a Slc26a4 Myo6 Pax3 Tecta Thrb Pmp22 Cdh23 Human disorder(s) Usher syndrome type 1F (USH1F) DFNA36, DFNB7/B11 Stickler syndrome type 2 (STL2) Osteogenesis imperfecta (OI) Stickler syndrome type 3 (STL3), DFNA13 Alport syndrome Stickler syndrome type 1 (STL1) WaardenburgShah syndrome (WS4) Piebald trait (PBT) Branchio-oto-renal syndrome (BOR) Craniosynostosis Hypoparathyroidism, sensorineural deafness and renal dysplasia syndrome (HDR) Jervell and LangeNielsen syndrome (JLNS2) Jervell and LangeNielsen syndrome (JLNS1) WaardenburgShah syndrome (WS4) Waardenburg syndrome type 2 (WS2), Tietz syndrome Norrie disease (ND) Renal-coloboma syndrome WaardenburgShah syndrome (WS4) DFN3 DFNA15 Charcot-Marie-Tooth disease type 4F (CMT4F) Usher syndrome type 1B (USH1B), DFNB2, DFNA11, atypical Usher syndrome DFNB3 Pendred syndrome (PDS), DFNB4 DFNA22 Waardenburg syndromes types 1 and 3 (WS1, WS3), Craniofacial dysmorphism, hand abnormalities, profound sensorineural deafness (CDHS) DFNA8/A12, DFNB21 Thyroid hormone resistance Charcot-Marie-Tooth disease type 1A (CMT1A) Usher syndrome type 1D (USH1D), DFNB12 References (103,104,128) (12,50) (81,129,130) (131134) (82,83) (23,135) (80,136,137) (111,138,139) (140142) (88,143,144) (145,146) (147,148) (91,92,149,150) (94,151,152) (86,153) (28,95,154,155) (13,14,156) (157,158) (87,159) (105, 160162) (69,163,164) (165) (7,9,98,166,167) (99,168) (17,109,169) (48,49) (27,101,102,170,171) (21,112,172) (173,174) (106,175,176) (10,11,177)

3277 had sequence similarity to other ESTs representing 2266 unique clusters; 778 categorized into 700 clusters had no sequence similarity to known genes or ESTs and can be considered to be cochlear-specic. Identication of additional known genes, ESTs and cochlear-specic ESTs provides new candidate genes for both syndromic and nonsyndromic deafness disorders. A variety of web resources have been developed for genetic and genomic studies of the auditory system that facilitate candidate gene approaches and are listed in Table 2. In addition to sequence-based approaches, gene expression chips provide an important means to explore the repertoire of cochlear messages in the normal and diseased state. Data from gene chip assays are available on the web for normal mouse cochlea for ages P2 and P32 (42). Several preferentially expressed cochlear genes, namely COCH (43) and OTOR (44,45), have been identied from the human fetal cochlear cDNA library; COCH was further shown to be responsible for a sensorineural deafness and vestibular disorder, DFNA9 (22). Various genes have been identied from a similar approach using mouse inner ear transcripts and include Otog (37), Ocn95 (46), Ush1c (30), Fdp (mouse homolog of OTOR) (47) and Strc (31); the human homolog of

Ush1c was found to underlie mutations in USH1C and of Strc to be etiologic in DFNB16.

Mouse models for discovery of hearing genes Identication of mouse models of specic forms of deafness is of great interest as the mouse is clearly the model organism of choice for the study of hearing loss in humans. The mouse cochlea is highly similar in structure to that of the human. Studies of mouse mutants from fetal to adult ages makes possible investigation into the pathology at developmental time points simply not possible in humans. Of particular relevance to understanding the pathobiology and underlying molecular mechanisms of genetic mutations is the ability to evaluate early developmental stages in mouse mutants because hair cell defects may result from degenerative processes secondary to a primary abnormality in another cell type. Although there has been tremendous progress in identifying genes underlying deafness, there are still relatively few mouse models (Table 3). In some instances, identication of the mouse mutation has greatly preceded detection of the human disorder (48,49),

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whereas in other cases discovery of the genetic basis for deafness has occurred concurrently (12,50). Positional cloning of deafness genes in the mouse is facilitated by the ability to breed large numbers of mice with the same mutation to narrow the interval for study. A large screen of inbred mouse strains by ABR threshold analyses at The Jackson Laboratory is currently underway, and likely to identify mutants that will lead to discovery of new genes and modifying genes for deafness (51). In addition, large numbers of new mouse mutants for investigating mammalian gene function including deafness are being generated rapidly through ENU mutagenesis (52). This chemical mutagenesis program also makes possible genedriven approaches to mouse mutants and using this approach, two missense and one stop mutation were recently identied in Gjb2, the most common cause of nonsyndromic deafness in the human population (53). Besides the spontaneous deaf mouse mutants and those generated from mutagenesis programs, a number of gene targeting experiments have been performed following identication of the human gene, and have provided valuable mouse mutants for investigation. As the human and mouse DNA sequencing projects are nished, the mouse human synteny maps will also become better dened and it will become increasingly easier to locate potential mouse mutants for mapped human deafness disorders.

GENE DISCOVERY IN THE AUDITORY SYSTEM: THE PATH TO IMPROVED DIAGNOSIS AND CLINICAL CARE
Inspection of the genes identied in hearing disorders and those among the gene lists from the EST sequencing projects reveals a great diversity of transcripts, perhaps not surprising due to the large variety of cells and complexity of the inner ear. The nding of a large percentage of cochlear ESTs not identied in any other tissue may indicate the existence of genes that are unique to the cochlea. Certainly, the great degree of genetic heterogeneity reected in the many different syndromes involving hearing loss and mapped loci is indicative of a large number of genes orchestrating the hearing process. Grouping the genes discovered to be etiologic in deafness disorders into functional categories begins the process of understanding their role in hearing. Knowledge of the pathways in which many of these genes function will be an exciting journey in hearing science; no doubt pathways exist that are not yet imagined. Another important aspect of gene discovery for deafness disorders is that it makes possible the development of diagnostic tests and accurate genetic counseling. Appropriate medical management and therapeutic options may be based on an understanding of the specic disorder. Gap junction proteins: the connexins Prominent among the group of genes are those encoding gap junctions. A somewhat surprising nding in the eld has been the prevalence of mutations in a single gene encoding the gapjunction protein connexin 26, GJB2, accounting for up to 50% of all cases of autosomal recessive prelingual deafness in tested populations (5465). Connexin 26 gap junctions are believed to play a critical role in the recycling of potassium ions from their

entry into hair cells during sensory transduction from the endolymph through to the stria vascularis, where other potassium channels pump potassium back into the endolymph. The gap junction itself, the connexon, is formed from six monomers of connexin and forms a pore between cells by binding with a connexon on an adjacent cell. Several recurrent mutations have been found in GJB2 (e.g. 35delG, 167delT, and 235delC), some with ethnic predilections. In addition to the recurrent mutations, the gene is small (681 bp) making it especially amenable for genetic testing. Screening for mutations in GJB2 has already emerged as the cornerstone of genetic testing for hearing loss and has been incorporated in some centers into the clinical work-up of infants who fail newborn hearing tests. The connexin-deafness homepage provides information on connexin mutations in deafness (Table 2). Besides GJB2, genes for other gap junction proteins have been found to be associated with hearing loss including GJB3 (26), GJB6 (66) and GJA1 (67). A curious nding in genetic testing of the deaf for GJB2 has been the frequent observation of heterozygosity for a mutation. Various explanations have been proposed including the possibility that the deafness was due to another gene or that there was a mutation in a non-coding region of GJB2 not evaluated in the test. Recent identication of a 342 kb deletion in the GJB6 gene (D(GJB6D13S1830)) as the second most frequent mutation causing prelingual deafness in the Spanish population may provide the sought after answer in many cases (68). GJB6 maps within the same chromosomal region as GJB2, and these recently published data suggest that mutations in the DFNB1 locus can result in a monogenic or digenic pattern of inheritance. Of note, the typical mutationdetection assays commonly in use may miss such large deletions. Genes for maintenance of hair cell function Another group of genes of intense interest are those required for survival of sensory hair cells. The POU domain transcription factor gene POU4F3 is required for terminal differentiation and maintenance of inner hair cells and an 8 bp deletion in the POU homeodomain results in progressive hearing loss in DFNA15 (69). Studies of such genes may result in valuable insight into the molecular triggers for hair cell degeneration. Loss of hair cells is presumed to be a fundamental cause of progressive age-related hearing loss (presbycusis) and an understanding of this degenerative process might provide the basis for therapeutic intervention. The recent nding of the transmembrane cochlear-expressed gene TMC1 uncovers a common cause of nonsyndromic recessive deafness in Pakistan and India at the DFNB7/B11 locus on chromosome 9 in bands q13q21; mutations in TMC1 account for the deafness phenotype in 5.4 3.0% of 230 families screened (12). Cloning of TMC1 resulted from an interesting genomicsbased approach that rst involved identication of a predicted gene (subsequently designated TMC2) on chromosome 20 with sequence similarity to query sequences in a tBLASTx analysis of a BAC from the linked genetic interval. TMC1 mutations were also found to be etiologic in DFNA36 (12) and in the mouse mutants deafness (dn) (12) and Beethoven (Bth) (50). It is predicted that TMC1 protein may mediate an ion-transport or channel function required for the normal function of hair cells.

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The recessive dn mutant displays no auditory response and has secondary hair cell degeneration and the dominant Bth mutant appears to have normally functioning hair cells prior to degeneration. Modier genes Molecular analyses of the auditory system have already yielded a number of genes in mice and humans that inuence the expression or function of other genes. Studies of these genes are certain to provide insight into the interaction of their gene products. Notable among the mouse genes are tub (tubby) and moth1 (modier of tubby hearing) (70), and dfw (deafwaddler) and mdfw (modier of deaf waddler) (71). Moth1 can worsen or prevent the hearing impairment in tubby, depending upon the type of moth1 allele and whether one or both copies of the allele are functional. One allele of Mdfw can protect dfw heterozygotes from hearing loss, whereas another is permissive for hearing loss in dfw heterozygotes. In humans, the locus for a modier gene (DFNM1) for the deafness haplotype in DFNB26 has been identied on chromosome 1 in band q24 (72). Mitochondrial genes A variety of mitochondrial disorders have been found to involve hearing loss, perhaps reecting the highly metabolic state of the hearing process (73). Of particular interest has been the A1555!G mutation in 12S rRNA that is recognized as the most frequent cause of aminoglycoside-induced deafness and as the etiology of a nonsyndromic deafness (74). In a recent study a nearly identical degree of mitochondrial dysfunction was observed in enucleated lymphoblastoid cells derived from both symptomatic and asymptomatic individuals from the same kindred (75) supporting the possibility of a nuclear gene in modifying the effect of the mutation. Investigations in hereditary deafness have revealed many lessons in genetics, foremost among them a sensory system with profound genotypic and phenotypic heterogeneity. Despite the recent tremendous successes in the genetics of deafness, our knowledge remains woefully incomplete. An astonishing number of deafness loci have been mapped in humans and mice, yet the genetic basis of many disorders remains unknown. Genomic approaches using a combination of methods of positional cloning, candidate genes and mouse models continue to yield new and novel genes providing valuable insight into the molecular basis of the process of hearing.

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