Autosomal recessive nonsyndromic hearing loss

A R T I C L E

Autosomal Recessive Nonsyndromic Hearing LossRACHEL A. SUNDSTROM, LUT VAN LAER, GUY VAN CAMP, AND RICHARD J.H. SMITH*

Nearly all genes for autosomal recessive nonsyndromal inherited hearing loss (ARNSHL) localized thus farcause prelingual severe to profound or profound hearing impairment. Of the 25 reported loci, most havebeen identified using single consanguineous families. Six of these genes have been cloned and encode avariety of proteins, including ion channels, extracellular matrix components, cytoskeletal components, andproteins essential for synaptic vesicular trafficking. One of these genes appears to be responsible forapproximately 50% of all congenital severe to profound or profound hearing loss in many world popula-tions, and mutations in two other genes can lead to either syndromic or nonsyndromic forms of deafness.The identification of additional genes that cause ARNSHL and elucidation of their function will refine ourunderstanding of auditory physiology at the molecular level. Am. J. Med. Genet. (Semin. Med. Genet.)89:123–129, 1999. Q 2000 Wiley-Liss, Inc.

KEY WORDS: GJB2; MYO7A; MYO15; PDS; OTOF; TECTA

INTRODUCTION

Hereditary hearing impairment affectsapproximately 1:2,000 newborn infantsand accounts for more than 50% of se-vere to profound or profound child-hood deafness [Morton, 1991; Marazitaet al., 1993; Cohen and Gorlin, 1995].It can occur with other pleiotropicmanifestations to form a recognizedphenotype (syndromic hearing loss,

SHL) or appear in isolation (nonsyn-dromic hearing loss, NSHL). NSHL ac-counts for approximately 70% of ge-netic deafness [Newton, 1985; Morton,1991]. It is almost exclusively mono-genic and highly heterogeneous. Thenumber of deafness-causing genes is es-timated to range from 50 to 100 [Mor-ton, 1991; Zbar et al., 1998].

In the early 1990s, scientiststhought that mapping these loci wouldbe a formidable challenge. Potentialproblems included recessive inheri-tance, the dearth of single families largeenough for linkage analysis, and ex-treme heterogeneity, precluding pool-ing of many small families. The use of ahomozygosity mapping strategy, how-ever, circumvented these issues. Ho-mozygosity mapping depends on pa-rental consanguinity to provide theassurance that hearing loss in the prog-eny results from recessive inheritance[Lander and Botstein, 1987]. Affectedchildren of consanguineous parentsshare a common region of many cen-timorgans around the disease locus byvirtue of common descent. Althoughother regions across the genome alsowill be homozygous by descent, theseregions vary from one affected child tothe next [Fukushima et al., 1995b].

Within each consanguineous fam-ily, the power of HM varies as the co-efficient of inbreeding, F. In general,the probability of homozygosity by de-scent, a, can be expressed in terms of F

and disease allele frequency (q) as a 4

(Fq)/(Fq + (1-F)q2), where Fq equalsthose who are affected and homozy-gous by descent, and (1-F)q2 equalsthose who are affected but not homo-zygous by descent (i.e., affected due torandom meeting of disease alleles). If qis small compared with F, a approxi-mates 1 [Lander and Botstein, 1987;Fukushima et al., 1995b]. Linked re-gions will be homozygous by descentwith probability a, while unlinked re-gions will be homozygous by descentwith probability F. The odds in favor oflinkage can be expressed as a/F and willvary as a function of disease allele fre-quency for various coefficients of in-breeding. If the frequency of each genethat causes autosomal recessive nonsyn-dromal hearing loss (ARNSHL) issmall, a approximates 1.

The lod score obtained from asingle child of a first-cousin marriagewhere F equals 1/16 is log10(16/1) 41.2. Each additional affected child in afirst-cousin sibship contributes ∼0.6 tothe lod score, meaning that four af-fected children are sufficient to localizea deafness-causing gene [Smith et al.,1998]. In contrast, in a nonconsanguin-eous union, a minimum of four grand-parents, two parents, and four affectedand 12 unaffected progeny are requiredto obtain a lod score of more than 3(SLINK Monte Carlo simulations usinga polymorphic marker with six alleles

Dr. Guy Van Camp (PhD) is an investiga-tor and docent working at the Depart-ment of Medical Genetics of the Univer-sity of Antwerp. Dr. Van Camp is Head ofthe Hereditary Hearing Loss ResearchUnit in the Department. Dr. RichardSmith is the Sterba Hearing Research Pro-fessor and Director of the Molecular Oto-laryngology Research Laboratories in theDepartment of Otolaryngology—Headand Neck Surgery. Both groups have ex-tensively collaborated since 1994, andare as a collaborative unit responsible forseveral gene localizations and identifica-tions for hearing loss over the past 6years. Rachel Sundstrom is a graduatestudent in the Interdepartmental Genet-ics PhD Program at the University ofIowa. She is doing her thesis work on re-cessive non-syndromic hearing loss in theMolecular Otolaryngology ResearchLaboratories. Dr. Lut van Laer (PhD) is apost-doctoral student working in Dr. VanCamp’s laboratory. She had identifiedthe DFNA5 gene in 1998 and her currentfocus is determining the function of theDFNA5 gene product.

Contract grant sponsor: NIH; Con-tract grant number: RO1-DC02842.

*Correspondence to: Departmentof Otolaryngology–Head and Heck Sur-gery, University of Iowa, Iowa City, IA52242. E-mail: [email protected]

AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.) 89:123–129 (1999)

© 2000 Wiley-Liss, Inc.

encoding the NSHL gene is fully pen-etrant) [Weeks et al., 1990]. Among re-gion of the world that deserve specialattention for HM of deafness-causinggenes are parts of Italy, the Middle East,northern Africa, and India.

AUTOSOMAL RECESSIVEGENE LOCALIZATIONS

To date, 25 ARNSHL loci have beenreported (Table I). Numerous loci havebeen identified on several chromo-somes (ch3 DFNB6, DFNB15; ch7D F N B 4 , D F N B 1 2 , D F N B 1 4 ,DFNB17; ch10 DFNB12, DFNB23;ch11 DFNB2, DFNB18, DFNB20,DFNB21, DFNB24), but there also areseveral chromosomes to which no locushas been mapped (1, 5, 6, 8, 12, 16, 20,22). Overlapping loci further compli-cate predictions of the number of genesrepresented. For example, DFNB7/11and DFNB8/10 map to overlapping in-tervals on chromosomes 9 and 21, re-spectively, suggesting that in each case,a single gene might have been giventwo locus designations. There is alsoone unusual example in which twochromosomal regions generate equallyhigh lod scores—DFNB15 maps toboth chromosome 3 and chromosome19. Whether this represents an exampleof digenic recessive inheritance or false-positive localization is not known.

Of the 25 reported ARNSHL loci,the typical phenotype is congenital(prelingual) nonprogressive severe toprofound or profound hearing loss.There are, two exceptions. DFNB8-affected persons have hearing loss be-ginning at the end of the first decade oflife and progressing to severe loss acrossall frequencies by age 14–16 [Veske etal., 1996]; DFNB13-affected personshave prelingual loss that is moderatelysevere and then becomes severe to pro-found or profound during the second tothird decades [Mustapha et al., 1998a].

DFNB1: GJB2, ANINTERCELLULAR CHANNEL

The first ARNSHL locus, DFNB1, wasidentified by Guilford et al. in 1994.These investigators verified linkage tochromosome region 13q12-13 in two

consanguineous ARNSHL familiesfrom Tunisia [Guilford et al., 1994b].Their report was followed by theidentification of other consanguine-ous families of differing ethnic originwhose deafness was linked to theDFNB1 locus [Scott et al., 1995;Brown et al., 1996], and of severalnonconsanguineous white families in

which the ARNSHL phenotype co-segregated with markers from region13q12-13 [Maw et al., 1995]. In theco-segregating white families, pheno-typic variation was observed bothwithin sibships and between genera-tions, suggesting that allelic heteroge-neity might exist at the DFNB1 locus.The discovery that a dominant form ofnon-syndromic hearing loss, DFNA3,also mapped to chromosome 13q12-13added further support to the hypothesisof allelic heterogeneity [Chaib et al.,1994].

While studying a family with au-tosomal dominant palmoplantar kerato-derma (PPK) and a dominant form ofcongenital sensorineural hearing loss,Kelsell et al. (1997) discovered a T-to-C transition in codon 34 of GJB2, a

TABLE I. Autosomal Recessive Loci for Nonsyndromic Hearing Loss*

Locus Localization Reference for gene localization

DFNB1 13q12 Guilford et al., 1994bDFNB2 11q13.5 Guilford et al., 1994aDFNB3 17p11.2 Friedman et al., 1995DFNB4 7q31 Baldwin et al., 1995DFNB5 14q12 Fukushima et al., 1995bDFNB6 3p14-p21 Fukushima et al., 1995aDFNB7 9q13-q21 Jain et al., 1995DFNB8 21q22 Veske et al., 1996DFNB9 2p22-p23 Chaïb et al., 1996aDFNB10 21q22.3 Bonne-Tamir et al., 1996DFNB11 9q13-q21 Scott et al., 1996DFNB12 10q21-q22 Chaïb et al., 1996aDFNB13 7q34-q36 Mustapha et al., 1998aDFNB14 7q31 Mustapha et al., 1998bDFNB15 3q21-q25 19p13 Chen et al., 1997DFNB16 15q21-q22 Campbell et al., 1997DFNB17 7q31 Greinwald et al., 1998DFNB18 11p14-p15.1 Jain et al., 1998DFNB19 18p11 Green et al., 1998DFNB20 11q25DFNB21 11q Mustapha et al., 1999DFNB22a Reserved

DFNB23a 10p11.2-q21 Smith (unpublished observations)

DFNB24a 11q23 Smith (unpublished observations)

DFNB25a 4p15.3-q12 Smith (unpublished observations)

*Adapted from the Hereditary Hearing Loss Homepage, March 1999; Van Camp G.,Smith R.J.H.; http://dnalab-www.uia.ac.be/dnalab/hhh/). All hearing loss is prelin-gual (congenital) in time of onset and severe to profound or profound in degree, withtwo exceptions—DFNB8 and DFNB13 (see text for details).aLocus reported to the HUGO nomenclature committee but not yet published.

Of the 25 reportedARNSHL loci, the typical

phenotype is congenital(prelingual) nonprogressive

severe to profound orprofound hearing loss.

124 AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.) ARTICLE

gene that encodes a gap junction pro-tein called connexin 26 (Cx26). Thissubstitution results in a Met-to-Thramino acid change that segregated withthe profound hearing loss but not withthe skin disorder in this family [Kelsellet al., 1997].

Prompted by the co-localization ofDFNB1 and DFNA3, three consan-guineous DFNB1 Pakistani familieswere screened for deafness-causing mu-tations in Cx26. In two families, a ho-mozygous G-to-A transition was iden-tified in codon 24; affected members inthe third family were homozygous for aG-to-A transition in codon 77. Bothmutations result in premature stopcodons (W24X and W77X, respec-tively). Coupled with immunohisto-chemical evidence that Cx26 is highlyexpressed in human cochlear cells, thesedata implicated Cx26 as a gene respon-sible for ARNSHL at the DFNB1 locus[Kelsell et al., 1997].

Cx26 is a member of a family ofhighly related proteins that form inter-cellular channels. All connexin genesshare a common architecture—eachprotein (13 of which are known in ro-dents) has four transmembrane, two ex-tracellular, and three cytoplasmic do-mains. Oligomerization of individualconnexins results in the formation of ahexameric torus called a connexon.Coupling of two transmembrane-bound connexons results in formationof an intracellular channel [Bruzzone etal., 1996].

Expression patterns, ion selectivity,and gating properties vary from con-nexon to connexon, depending on theconstituent connexins. Cx26 is ubiqui-tously expressed, and in the inner ear, itis found in the nonsensory epithelialcells in the organ of Corti [Kikuchi etal., 1995]. Its presumed function is inthe potassium-recycling pathway, anessential component of auditory physi-ology if the high endolymphatic potas-sium concentration is to be maintained.

Prevalence studies of Cx26 muta-tions in persons with severe to pro-found or profound ARNSHL haveshown two unexpected findings. First,in a large number of ethnically differentpopulations throughout the world,Cx26 mutations are responsible for

more than half of the cases of ARNSHL[Estivill et al., 1998; Kelley et al., 1998;Green et al., 1999]. Second, in manyof these populations, a single muta-tion, the 35delG, predominates [Estivillet al., 1998; Kelley et al., 1998; Greenet al., 1999; Scott et al., 1998]. Thesedata have ignited a flurry of interest inCx26 screening as a clinical aid to thediagnosis of ARNSHL, which at pre-sent is a diagnosis of exclusion. The de-velopment of reliable DNA-based test-ing for common types of ARNSHLwould be valuable to the clinician andwould afford genetic counselors thenecessary information to provide betterrecurrence-risk data to parents of ahearing-impaired child.

DFNB2: MYO7A, ANUNCONVENTIONALMYOSINIn 1994, Guilford et al. localized anARNSHL gene to chromosome 11qand speculated that it was the homo-logue of the mouse shaker-1 gene[Guilford et al., 1994a]. Three yearslater, this speculation was confirmed[Weil et al., 1997]. The gene, myosin7a (MYO7A), is an unconventionalmyosin with expression restricted to thehair cells of the organ of Corti. Withinthe inner and outer hair cells, MYO7Ais found in the stereocilia, cuticularplate, and cell body, with largeramounts in the inner hair cell body thanin the outer hair cell body. In additionto causing DFNB2, mutations inMYO7A also cause USH1B andDFNA11.

In mammals, MYO7A is expressedalong the entire length of the stereocilia[Hasson et al., 1995], but in frogs, ex-pression is enriched in a band near thebottom of the stereocilia [Hasson et al.,1997]. This band, termed the basaltapers or ankle region, corresponds ul-trastructurally to a decrease in the num-ber of bundled actin filaments beforetheir insertion into the cuticular plate[Hasson et al., 1997]. This localizationsuggests that the structural role ofMYO7A is to provide a bridge betweenthe actin core of stereocilia and extra-cellular linkages that join stereocilia toensure bundle rigidity [Hasson et al.,1997].

Sequence analysis of the 48 codingexons of MYO7A in the family withDFNB2 disclosed a G-to-A transitionat the last nucleotide of exon 15, result-ing in a Met-to-Ile change [Weil et al.,1997]. Both amino acids have a similarcharge and positive hydropathic index[Kyte and Doolittle, 1982], and thisparticular methionine residue is neitherhighly conserved nor part of the actin-binding site itself, making it unlikelythat this amino acid change impairs ac-tin-binding properties of MYO7A. Thelocation of this mutation at the lastnucleotide of an exon, however, canaffect splicing efficiency [Weil et al.,1997].

In the DFNB2-affected patients,skipping of exon 15 from the maturetranscript results in a 46-amino-acid in-frame deletion. Assuming that splicingefficiency is reduced equally in the earand eye, comparison of the USH1B andDFNB2 phenotypes suggests that theeye is less sensitive than the ear to adecrease in MYO7A function, suggest-ing a dosage effect. Mutations inMYO7A that result in a dominantnegative effect cause DFNB11 [Liu etal., 1997].

DFNB3: MYO15, ANOTHERUNCONVENTIONALMYSOIN

Two percent of the residents ofBengkala, Bali, have ARNSHL. In1995, Friedman et al. used a direct ge-nome-wide disequilibrium search strat-egy to localize the deafness-causinggene in this population. The locus,DFNB3, mapped to chromosome 17,and, on the basis of conserved synteny,the mouse mutant shaker-2 was pro-posed as its murine equivalent [Fried-man et al., 1995; Liang et al., 1998].

An in vivo experimental comple-mentation approach was used to narrowthe shaker-2 critical region and identifya bacterial artificial chromosome (BAC)clone that would rescue the shaker-2phenotype [Probst et al., 1998]. Se-quence data generated from this BACwere analyzed with GENSCAN,

ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.) 125

GRAIL, and BLAST, and a novel un-conventional myosin was identified anddesignated myosin 15 (MYO15). Mu-tation screening of the coding regionshowed two missense mutations, an A-to-T transition in codon 892 (I892P)and an A-to-T transition in exon 28(N890Y) in two different DFNB3families. One nonsense mutation, an A-to-T transition in exon 39 (K1300X)was detected in a third DFNB3 family[Wang et al., 1998]. Scanning electronmicroscopy of the luminal surface of in-ner hair cells in 1-month-old sh2/sh2mouse mutants suggests that MYO15 isinvolved in the maintenance of actinorganization in the hair cells of the or-gan of Corti [Probst et al., 1998].

DFNB4: PDS, A CHLORIDEAND IODIDETRANSPORTER

In 1995, Baldwin et al. localized thefourth ARNSHL gene on chromosome7. One year later, Coyle et al. [1996]and Sheffield et al. [1996] showed thatthe gene for Pendred syndrome co-localized with DFNB4. The followingyear, using a positional cloning strategy,

Everett et al. [1997] cloned the Pendredsyndrome gene (PDS) and named thepredicted protein “pendrin.” Subse-quent reanalysis of the original DFNB4family documented goiters in some af-fected individuals, altering the diagnosisto Pendred syndrome rather than a typeof nonsyndromic hearing loss. Anotherlarge consanguineous family has beenidentified in which affected individualshave profound prelingual sensorineuralhearing impairment, dilation of the ves-tibular aqueduct, and normal thyroidfunction without goiter. The disease-causing gene in this family mapped tothe DFNB4 locus and mutations wereidentified in the PDS gene [Li et al.,1998]. These data suggest that allelicvariations of PDS can be associatedwith either syndromic or nonsyn-dromic hearing impairment. Functionalstudies of pendrin have shown that al-though it shares homology with a classof sulfate transporters, pendrin does nottransport sulfate but rather iodide andchloride [Scott et al., 1999]. In situ hy-bridization showing PDS expression inthe outer sulcus cells of the organ ofCorti suggests its role in maintainingendolymphatic fluid balance.

DFNB9: OTOF, ENCODES AFER-1-LIKE PROTEIN

In 1996, Chaıb et al. localized the ninthARNSHL gene on chromosome 2p22-23 [Chaib et al., 1996]. Subsequentidentification of additional families per-mitted refinement of the DFNB9 inter-val to a 1-centimorgan region boundedby D2S158 and D2S174 [Yasunaga etal., 1999]. Expressed sequence tagswithin this interval were submitted torounds of extension by 58-RACE poly-merase chain reaction using total fetalmRNA, and predicted amino acid se-quences were compared to sequencesderived from clones previously isolatedfrom subtracted mouse cochlear cDNAlibraries [Yasunaga et al., 1999].

The deduced amino acid sequenceof one of these extended clones showed89.7% identity and 97.1% similarity tothe predicted sequence of 205 aminoacids encoded by a mouse cochlearcDNA clone. The reconstituted cDNAsequence encoded a protein of 1,230amino acids with three C2 domains andsignificant homology to spermatogene-sis factor FER-1 in C. elegans. The

TABLE II. Summary of Genes Causing ARNSHL*

Locus Gene Function MutationsMousemodels

Relateddeafness loci

Affectedpopulations

DFNB1 GJB2 Connexin 26, gapjunction protein

35delG accounts for 85%of GJB2 mutations;numerous othermutations found

None DFNA3 Numerousworldwide

DFNB2 MYO7A Myosin 7a, possiblestructural role

G→A in last nucleotideof exon 15

shaker-1 USH1B,DFNA11

Tunisian

DFNB3 MYO15 Myosin 15, maintainingactin organization inhair cells

I892F, N890Y, K1300X shaker-2 None Bengkala,Indian

DFNB4 PDS Pendrin, chloride andiodide transporter

G497S None PendredSyndrome

Indian

DFNB9 OTOF Otoferlin, synapticvesicle trafficking

T→A in exon 18 (Y→X) None None Lebanese

DFNB21 TECTA a-tectorin, componentof the tectorialmembrane

G→A/intron 9 donor siteskipping of exon 9

None DFNA8/12 Lebanese

*ARNSHL, autosomal recessive nonsyndromic hearing loss.


novel protein was named otoferlin(OTOF) [Yasunaga et al., 1999].

OTOF extends over 21 kb andcontains 28 coding exons. Analysis ofthe expression pattern of OTOF in mu-rine inner ear by in situ hybridizationshows labeling mainly in inner hair cellsand vestibular type 1 sensory cells. Thisfinding and the impaired cellular pro-cess in C. elegans FER-1 mutants sug-gest that OTOF is involved in Ca2+-triggered vesicle membrane fusions. Infour affected families, a T-to-A trans-version was identified in exon 18 thatsubstitutes a tyrosine codon for a stopcodon [Yasunaga et al., 1999].

DFNB21: TECTA ENCODESA COMPONENT OF THETECTORIAL MEMBRANE

In 1999, Mustapha et al. localized thetwenty-first ARNSHL gene. It mappedto a region of chromosome 11q23-25known to include TECTA, the genethat encodes a-tectorin [Verhoeven etal., 1998]. This 2,155-amino-acid pro-tein is a component of the tectorialmembrane [Legan et al., 1997]. Muta-tions in TECTA cause ADNSHL(DFNA8/12), and sequence analysis ofthe DFNB21-affected family showed aG-to-A transition in the donor splicesite (GT) of intron 9, predicted to leadto a truncated protein of 921 amino ac-ids [Mustapha et al., 1999]. This findingmeans that allele variants of TECTAcan cause either autosomal dominant orautosomal recessive NSHL. Based onthe normal auditory function of theheterozygous carriers in the DFNB21family, it appears that approximately50% of the normal amount of a-tec-torin is sufficient to preserve both me-chanical and electrical properties of thetectorial membrane [Mustapha et al.,1999]. This observation also impliesthat the hearing loss in DFNA8/12-affected individuals is the result of adominant negative effect.

CONCLUSION

Auditory function is an extraordinarilycomplex process. Requisite compo-nents can be identified and isolated on a

gene-by-gene basis by focusing onARNSHL. Six such genes have beencloned to date, encoding ion channels,extracellular matrix components, cyto-skeletal components, and proteins es-sential for synaptic vesicular trafficking(Table II).

Surprisingly, mutations in GJB2appear to be responsible for half of se-vere to profound and profound deafnessin many populations, and mutations inMYO7A and PDS cause either SHL orNSHL. With GJB2 mutations account-ing for a significant proportion ofARNSHL, the large number of re-maining deafness loci makes it unlikelythat another gene will be found as acommon cause of recessive deafness.This opinion is indirectly supported bythe observation that at present only afew loci have more than one linkedfamily. The use of homozygosity map-ping thus becomes increasingly impor-tant as the method of choice for local-izing genes that affect auditoryfunction. The localization and cloningof these genes will complement the pic-ture of inner ear function that is begin-ning to emerge at the molecular level.

ACKNOWLEDGMENTS

G.V.C. holds a research position withthe FWO (Flemish Fonds voor Weten-schappelijk Onderzoek); R.J.H.S. issupported in part by RO1-DC02842.

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Auditory function is anextraordinarily complex

process. Requisitecomponents can be

identified and isolated on agene-by-gene basis by

focusing on ARNSHL.


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Autosomal recessive nonsyndromic hearing loss