Hearing Research 130 (1999) 1^6

Review

The role of mouse mutants in the identi¢cation of human hereditary
hearing loss genes
Frank J. Probst, Sally A. Camper *
Department of Human Genetics, 4301 MSRB III, 1500 W. Medical Center Drive, The University of Michigan, Ann Arbor, MI 48109-0638, USA
Received 1 August 1998; received in revised form 28 November 1998; accepted 6 December 1998

Abstract
The mouse is the model organism for the study of hearing loss in mammals. In recent years, the identification of five different
mutated genes in the mouse (Pax3, Mitf, Myo7a, Pou4f3, and Myo15) has led directly to the identification of mutations in families
with either congenital sensorineural deafness or progressive sensorineural hearing loss. Each of these cases is reviewed here. In
addition to providing a powerful gateway to the identification of human hearing loss genes, the study of mouse deafness mutants can
lead to the discovery of critical components of the auditory system. Given the availability of several mouse mutants that affect
possible homologues of other human deafness genes, it is likely that the mouse will play a key role in identifying other human hearing
loss genes in the years to come. z 1999 Published by Elsevier Science B.V. All rights reserved.
Key words: Deafness; Mouse; Waardenburg syndrome; Usher syndrome

1. Introduction
The mouse has long been used as a model organism
to emulate various human diseases. Conversely, many
human diseases have been discovered for which mouse
mutations were already known. In many ways, the genetics of the mouse are much more tractable than those
of the human. The relatively short generation time of
mice and the ability to generate crosses with inbred
strains of mice so that all of the progeny are genetically
informative facilitate the rapid construction of well-de¢ned genetic maps. The application of transgene technology can further expedite gene identi¢cation. Phenotypic analysis can be carried out on mice due to the
accessibility of tissue from early development throughout adult life.
Mice have been useful for the cloning of several human genes involved in hereditary hearing loss. Five
genes responsible for 10 di¡erent human conditions

have all been cloned as a direct result of the discovery
of the mutated homologous mouse gene (Table 1).
Genes for human hearing loss have been di¤cult to
clone in the past, but they are now being identi¢ed at
a rapid pace. The ¢rst autosomal mutations for nonsyndromic sensorineural hearing loss were not discovered until 1997. Since that time, mutations in nine additional genes have been identi¢ed which all cause
nonsyndromic sensorineural hearing loss. Still, there
are more than 30 known nonsyndromic hearing loss
loci for which the causative gene has yet to be identi¢ed
(Van Camp and Smith, 1998), and many of these loci
have potential mouse counterparts. We discuss here the
use of mouse mutants in ¢nding ¢ve human hearing
loss genes and the potential for the mouse to aid in
the discovery of other human hearing loss loci. Additional mouse and human hearing loss genes are reviewed in Steel, 1995 and Kalatzis and Petit, 1998.
2. splotch

* Corresponding author. Tel.: +1 (734) 763-0682;
Fax: +1 (734) 763-7672; E-mail: scamper@umich.edu

The mouse splotch (Sp) mutation arose spontaneously on an inbred strain of mice in 1947 (Russell,

0378-5955 / 99 / $ ^ see front matter ß 1999 Published by Elsevier Science B.V. All rights reserved.
PII: S 0 3 7 8 - 5 9 5 5 ( 9 8 ) 0 0 2 3 1 - 7

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F.J. Probst, S.A. Camper / Hearing Research 130 (1999) 1^6

2

Table 1
Mouse mutants that have led to the identi¢cation of human hearing
loss genes
Mouse mutant

Defective gene

splotch (Sp)
Pax3
microphthalmia (mi) Mitf
shaker-1 (sh1)
Myo7a
Pou4f3
Pou4f33a3
shaker-2 (sh2)
Myo15

Human phenotype(s)
WS1, WS3, CDHS
WS2, Tietz syndrome
USH1B, DFNB2, DFNA11
DFNA15
DFNB3

1947) and was mapped to mouse chromosome 1 in 1954
(Snell et al., 1954). Sp heterozygotes have a white belly
patch, white feet, and a white tail tip, as melanocytes
fail to migrate to these regions during development. Sp
homozygotes die in utero, with most exhibiting spina
bi¢da and/or exencephaly due to a failure of the closing
of the neural tube (Moase and Trasler, 1992). The inner
ears of these homozygous embryos are often malformed, though this result appears to be secondary to
the neural tube defect (Deol, 1966). The gene mutated
in Sp mice was found to be Pax3, a paired homeodomain transcription factor (Epstein et al., 1991, 1993).
Pax3 is expressed along the dorsal side of the neural
tube, in the brain, and in neural crest cell derivatives
(including melanocytes) (Goulding et al., 1991), which
is consistent with the phenotype seen in the mice.
Based on the similarity of the phenotype, splotch was
suggested as a mouse model of the human Waardenburg syndrome type 1 (WS1, OMIM-193500) (Asher
and Friedman, 1990). WS1 can be associated with a
constellation of di¡erent symptoms, but there are six
which form the key to diagnosis: (1) dystopia canthorum (i.e. lateral displacement of the inner edges of the
eyes), (2) a broad nasal root, (3) hypertrichosis of the
medial ends of the eyebrows (i.e. monobrow), (4) hypopigmentation of the skin and head hair, (5) total or
partial heterochromia iridis (i.e. di¡erently colored
eyes), and (6) congenital unilateral or bilateral deafness
(Waardenburg, 1951; Arias, 1971; Asher and Friedman, 1990). WS1 was mapped to human chromosome
2q by two di¡erent groups (Foy et al., 1990; Asher et
al., 1991). Based on conserved synteny, PAX3, the human homologue of the mouse Pax3 gene was predicted
to map to this same region of human chromosome 2q
(Epstein et al., 1991). Mutations in several WS1 patients were found in PAX3, indicating that PAX3
is indeed the gene responsible for this disorder (Tassabehji et al., 1992; Baldwin et al., 1992; Morell et al.,
1992).
A missense mutation in PAX3 was also found in
patients with Klein-Waardenburg syndrome (WS3,
OMIM-148820). WS3 patients have limb abnormalities
in addition to the symptoms seen in WS1 (Hoth et al.,
1993). This ¢nding clearly demonstrates that di¡erent
mutations in PAX3 can produce distinct phenotypes

leading to clinical classi¢cation as separate syndromes.
Indeed, a di¡erent missense mutation a¡ecting the same
amino acid residue was later found to cause craniofacial-deafness-hand syndrome (CDHS, OMIM-122880),
a more severe disorder than WS3 (Asher et al., 1996).
Individuals with CDHS have marked craniofacial dysmorphism, hand abnormalities, and profound sensorineural deafness (Sommer et al., 1983).
Clearly, di¡erent mutations in PAX3 can lead to a
wide range of phenotypes. The deafness that may be
seen in individuals with any of the three disorders
above presumably results from a failure of melanocytes
to properly migrate to the inner ear during development. Melanocytes are necessary for the proper functioning of the cochlea, as they form part of the stria
vascularis, which produces the endocochlear potential
in the inner ear (Steel and Barkway, 1989).
3. microphthalmia
Another example of a link between pigmentation and
deafness is microphthalmia (mi). The original mi mutation was found in the progeny of an X-ray irradiated
mouse. Heterozygotes have white spotting on the belly,
head, and tail, while homozygotes are white and microphthalmic (Hertwig, 1942). In addition, inner ear defects are associated with some alleles of mi (Deol,
1967 ; Steingrimsson et al., 1994). The gene responsible
for mi was cloned in 1993 and shown to be a basichelix-loop-helix-leucine zipper type of transcription factor that is expressed in the developing eye, ear, and
skin. As in the splotch mouse, melanocyte migration
appears to be defective as a result of mutations in this
gene, thus resulting in the mutant phenotype (Hodgkinson et al., 1993).
Even before it was cloned, the mouse mi gene was
suggested as a candidate gene for Waardenburg syndrome (Asher and Friedman, 1990). When Waardenburg syndrome type 2 (WS2, OMIM-193510) was
mapped to the short arm of chromosome 3, it was
noted that MITF, the human homologue of the mi
gene, mapped to this same region (Hughes et al.,
1994). The major di¡erence between WS1 and WS2 is
that WS2 patients do not exhibit dystopia canthorum
(Hageman and Delleman, 1977). Splice site mutations
in MITF were soon found in a¡ected individuals
from two unrelated pedigrees, demonstrating that
MITF is the causative gene in WS2 (Tassabehji et al.,
1994).
A di¡erent mutation in this same gene was also
found to cause Tietz syndrome (OMIM-103500) (Smith
et al., 1997). Individuals with this autosomal dominantly inherited condition all have mild albinism, blond
hair, blue eyes, and profound congenital deafness
(Tietz, 1963).

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4. shaker-1
The mouse shaker-1 (sh1) mutation arose spontaneously in 1929 (Lord and Gates, 1929). sh1/sh1 mice are
deaf and exhibit head-tossing and circling behaviors,
presumably as a result of associated vestibular defects.
In the early 1990s, sh1 was shown to be tightly linked to
the olfactory marker protein gene (Omp1) (Brown et al.,
1992). A nearby myosin gene, Myo7a, was soon discovered via positional cloning, and mutations in this gene
were identi¢ed in three di¡erent strains of shaker-1 mice
(Gibson et al., 1995).
It was known at that time that a gene for Usher
syndrome type 1B (USH1B, OMIM-276903) (deafness
and retinitis pigmentosa) maps to the homologous region in the human (Kimberling et al., 1992; Smith et
al., 1992). Mutations in the human gene, MYO7A, were
found in ¢ve unrelated individuals with Usher syndrome type 1B (Weil et al., 1995). To date, 28 di¡erent
mutations in MYO7A have been identi¢ed in patients
with this disorder (Weston et al., 1996; Levy et al.,
1997 ; Adato et al., 1997; Liu et al., 1997c).
In addition to the Usher 1B phenotype, di¡erent
mutations in MYO7A can result in sensorineural deafness without any associated visual defects. The DFNB2
locus for autosomal recessive nonsyndromic hearing
loss (OMIM-600060) was mapped to the same region
of human chromosome 11 as USH1B. Homozygous
individuals lose their hearing between birth and 16
years of age, and some experience vertigo, but there
are no other symptoms (Guilford et al., 1994). A splicing mutation was found in the MYO7A gene of these
individuals (Weil et al., 1997), and both a splicing mutation and a missense mutation were found in two unrelated Chinese families with a similar phenotype (Liu
et al., 1997a). As these mutations preserve MYO7A's
retinal function, they must either a¡ect di¡erent isoforms that those a¡ected in USH1B patients, or else
they disrupt regions of the gene which are not critical
for MYO7A's role in the retina. Alternatively, it is possible that these individuals have a mild, undiagnosed
retinal defect, or that retinal defects only develop on
certain genetic backgrounds.
DFNA11 (OMIM-601317), a locus for autosomal
dominant postlingual (i.e. after language acquisition)
progressive sensorineural hearing loss was also mapped
to this same region (Tamagawa et al., 1996). A¡ected
individuals were shown to have a 9 bp deletion in the
coiled-coil domain of MYO7A. Since the coiled-coil
domain of this protein is involved in dimerization, it
has been proposed that this mutation has a dominantnegative e¡ect, possibly because mutant monomers of
MYO7A bind to normal monomers and create an abnormal dimer. This would account for DFNA11's autosomal dominant inheritance pattern (Liu et al., 1997b).
Scanning electron microscopy of the surface of the

3

organ of Corti of Myo7aTt and Myo7aVITf homozygous mice shows disorganization of the stereociliary
bundles on the hair cells, suggesting that one of
Myo7a's roles is to ensure the proper organization of
stereocilia on the apical surfaces these cells. However,
the stereocilia on the hair cells of Myo7ashI /shI mice are
fairly well organized, and these mice still have severe
hearing de¢cits, which suggests that Myo7a must have
additional functions in the inner ear which are critical
for normal hearing (Self et al., 1998). Such experiments
are problematic in humans due to the di¤culty of obtaining fresh autopsy specimens for study. By contrast,
cochleas from mutant mice can be obtained at any developmental stage to aid in the understanding the function of the mutated gene.
3a3
5. Pou4f33a3

The mouse Pou4f3 gene (also known as Brn3.1) encodes a class IV POU domain transcription factor that
is expressed in the hair cells of the auditory and vestibular systems. Two di¡erent groups have engineered
mice with targeted deletions of this gene. Both groups
report that mice homozygous for the targeted deletion
of Pou4f3 are deaf and have balance defects. Histological studies of these mice showed a complete absence of
hair cells in the cochlea, demonstrating that Pou4f3 is
necessary for either the di¡erentiation or maintenance
of these cells (Erkman et al., 1996 ; Xiang et al., 1997).
The Pou4f3 gene is located on mouse chromosome 18
(Theil et al., 1994) in a region that shows synteny homology with human chromosomes 5 and 18 (Copeland
et al., 1993).
DFNA15, an autosomal dominant nonsyndromic
hearing loss locus (OMIM-602459), was mapped to a
25 cM region on human chromosome 5. Hearing loss in
a¡ected family members typically begins between the
ages of 18 and 30 and progresses to a moderate to
severe hearing loss by age 50. An 8 bp deletion was
found in one of the two copies of the POU4F3 gene
in all a¡ected individuals. It is not yet clear whether this
is a dominant negative mutation or if haploinsu¤ciency
of POU4F3 is the cause of the hearing loss (Vahava et
al., 1998).
6. shaker-2
The shaker-2 (sh2) mouse arose in 1928 in the progeny of an X-ray irradiated mouse (Dobrovolskaia-Zavasdkaia, 1928). Homozygous mice do not startle to
sound and demonstrate circling behavior. This mutation was mapped to mouse chromosome 11 (Snell and
Law, 1939), and ¢ne-mapping of the locus placed sh2 in
a region of mouse chromosome 11 with synteny homol-

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ogy to human chromosome 17 (Wakabayashi et al.,
1997 ; Liang et al., 1998). The deafness and circling in
sh2 mice has been corrected with a large BAC (bacterial
arti¢cial chromosome) transgene. This transgene was
shown to contain a novel unconventional myosin
gene, Myo15. sh2 mice have a missense mutation in
Myo15 that converts a highly conserved cysteine residue
to a bulky tyrosine residue, which disrupts the function
of the protein and accounts for the phenotype (Probst
et al., 1998; Wakabayashi et al., 1998).
DFNB3, a locus for nonsyndromic autosomal congenital deafness (OMIM-600316), was mapped to chromosome 17p in a large kindred from a village on the
island of Bali. Congenital deafness has been present for
so long and at such a high frequency in this village that
a village-speci¢c sign language has evolved (Friedman
et al., 1995). All a¡ected individuals were shown to be
homozygous for a missense mutation in MYO15. Missense and nonsense mutations were also detected in this
gene in two unrelated Indian families that were segregating nonsyndromic autosomal recessive congenital
deafness (Wang et al., 1998).
The function of Myo15 in the inner ear is unknown,
but sh2/sh2 mice have markedly short stereocilia on
both the outer and inner hair cells in the cochlea.
This raises the possibility that Myo15 is involved directly or indirectly in extending or maintaining the stereocilia of these cells. This may involve transportation of
actin or actin-bound proteins toward the apical surface
of the hair cells and into the stereocilia. In sh2/sh2 mice,
an actin-containing structure extends from the base of
each inner hair cell towards the ganglion layer of the
cochlea, further supporting the theory that Myo15 is
essential for normal actin organization within the inner
hair cells of the cochlea (Probst et al., 1998).
7. Conclusion
Mouse mutants have been critical for discovering a
number of genes that result in human hereditary hearing loss. As there are 12 additional mouse deafness loci
with possible homology to human hearing loss loci, the
potential for the mouse to contribute further to the
discovery of human hearing loss genes is quite high
(Van Camp and Smith, 1998) (Table 2). When a mouse
model is available for a human hereditary disease of
unknown genetic etiology, it is almost always most expedient to clone the mouse gene in order to clone the
human gene. Thus, some of these mouse mutants will
almost certainly lead to the discovery of more human
hearing loss genes. Progress in the mouse genome e¡ort
now permits a rapid progression from genetic maps to
complete physical maps of the critical regions of mutant
mouse genes. Transgene technology can now further
narrow the critical region via complementation studies,

Table 2
Mouse mutants with possible homology to human hearing loss loci
(Van Camp and Smith, 1998)
Mouse mutant

Potential human homologue(s)

Ames waltzer (av)
Bronx waltzer (bv)
dancer (Dc)
deafness (dn)
dreher (dr)
gyro (Gy)
Jackson circler (jc)
loop-tail (Lp)
mocha (mh)
Nijmegen waltzer (nv)
spinner (sr)
waltzer (v)

DFNB12, USH1D
DFNA6
DFNA2
DFNB7, DFNB11
DFNA7
DFN6
DFNB12, USH1D
DFNA7
DFNB12, DFNB8, DFNB10, USH1D
DFNA4
DFNB6
DFNB12, USH1D

The DFNA, DFNB, and DFN loci cause autosomal dominant, autosomal recessive, and X-linked nonsyndromic hearing loss, respectively.

cutting years o¡ of positional cloning e¡orts. Finally,
high throughput DNA sequencing and high density
EST maps can obviate the necessity of laborious gene
identi¢cation methods. We have reached an exciting era
where technological improvements will help us unlock
the secrets of dozens of additional genes that are critical
for the process of hearing.
Acknowledgments
We thank Karen Steel of the MRC Institute of Hearing Research, Karen Avraham of Tel Aviv University,
Thomas Friedman and Konrad Noben-Trauth of the
National Institute on Deafness and Other Communication Disorders, and Donna Martin and Yehoash Raphael of the University of Michigan for their advice and
suggestions. This work was supported by the National
Institute of Child Health and Human Development
R01 HD30428 (S.A.C.), the National Science Foundation (F.J.P.), NIGMS T32 GM07863 (F.J.P.), and a
University of Michigan Rackham Graduate Fellowship
(F.J.P.).
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