TITLE: Genetic Hearing Loss
SOURCE: Grand Rounds Presentation, UTMB, Dept. of Otolaryngology
DATE: March 17, 2004
RESIDENT PHYSICIAN: Jing Shen
FACULTY PHYSICIAN: Ronald W. Deskin, MD
SERIES EDITORS: Francis B. Quinn, Jr., MD and Matthew W. Ryan, MD
"This
material was prepared by resident physicians in partial fulfillment of
educational requirements established for the Postgraduate Training Program of
the UTMB Department of Otolaryngology/Head and Neck Surgery and was not
intended for clinical use in its present form. It was prepared for the purpose
of stimulating group discussion in a conference setting. No warranties, either
express or implied, are made with respect to its accuracy, completeness, or
timeliness. The material does not necessarily reflect the current or past
opinions of members of the UTMB faculty and should not be used for purposes of
diagnosis or treatment without consulting appropriate literature sources and
informed professional opinion."
INTRODUCTION
Hearing loss is the most common sensory deficit in humans. Roughly one child in a thousand is born with
hearing impairment significant enough to compromise the development of normal
language skills. Hearing loss can be
caused by environmental factors as well as genetic factors. Environmental causes include pre- and post
natal infection and ototoxic drug exposure.
But it is estimated that 50% to 75% of all childhood deafness is due to
hereditary causes. There are two main
forms of genetic hearing loss, syndromic and nonsyndromic. Children with syndromic hearing loss have
other clinical features in addition to the hearing loss. About 15-30% of the hereditary hearing loss
is syndromic, while the vast majority is nonsyndromic (70%).
Hereditary hearing loss can be transmitted
in several inheritance patterns, including autosomal dominant, autosomal
recessive, X-linked inheritance and mitochondrial inheritance. Briefly, autosomal dominant inheritance
exhibits a vertical pattern of transmission.
Only one altered gene is needed for an individual to be affected. The offspring has 50% chance to receive the
copy of the mutated gene from the affected parent. The most common pattern of transmission in
hereditary hearing loss is autosomal recessive.
A child must have both copies of the mutated gene to exhibit
deafness. The parents will most likely
have normal or near normal hearing even though they possess the recessive
gene. Typically there is a 25% chance
that the offspring will be affected and manifest hearing impairment or deafness. This mode of transmission has a horizontal
pattern. The X-linked inheritance
involves particular genes located on the X chromosome. It more commonly affects male because they
possess a single X chromosome and will present phenotypically with any mutation
on the X chromosome. Female can carry
the mutation on one of the X chromosomes without phenotypic expression. Her sons have a 50% chance of inheriting the
mutation and express phenotypically. The
daughters have a 50% chance of inheriting the mutation and become a carrier of
the mutation. Mitochondrial inheritance is caused by mutations in the
mitochondrion DNA, small loop of DNA in mitochondrion. Only mothers can pass on the mutation because
only the eggs carry mitochondrion DNA.
When two genetic loci lie near each
other on a chromosome, they tend to be inherited together. Based on this principle, genetic
linkage analysis is used to localize the disease gene to a specific region on a
specific chromosome. There are also hundreds of mouse models available for
studying genetic hearing loss. Each
provides a piece of the puzzle in our understanding of inner ear biology. Some are directly relevant to human deafness
and others provide key elements in the development and function of sensory
structures of the ear.
Hereditary deafness is genetically a
highly heterogeneous disease with many different genes responsible for auditory
dysfunction. Genetic heterogeneity has
been observed repeatedly in our improved understanding of syndromic hearing loss. Mutations of several different genes can
cause the identical clinical phenotype.
On the other hand, different mutations in one gene can cause variable
phenotypes.
Syndromic hearing loss
There are over four hundreds syndromes
with hearing loss have been described.
The Online Mendelian Inheritance in Man (www.ncbi.nlm.nih.gov/Omim) has
comprehensive descriptions of the clinical features and molecular genetics of
these syndromes as well as an all-inclusive list of references.
Alport syndrome
It is a hereditary disorder of basement membranes. Majority of the cases are inherited in an X-linked manner (80%). Autosomal recessive as well as autosomal dominant inheritance has also been observed. It is characterized by the association of renal dysfunction with hearing loss. Symptoms include high frequency sensorineural hearing loss, hematuria with progressive renal failure, and ocular abnormalities. Microscopic hematuria was found to be the most reliable urinary criterion of hereditary nephritis in both males and females. The hematuria was often accompanied by red cell casts, indicating that the renal lesion is a glomerulitis. Men were more severely affected than women. They had striking urinary abnormalities in early childhood which progressed to renal failure in adulthood. Affected women had less obvious urinary findings and rarely developed uremia. Typical ocular associations are a dot-and-fleck retinopathy, which occurs in approximately 85% of affected adult males, anterior lenticonus, which occurs in approximately 25%, and the rare posterior polymorphous corneal dystrophy.
Mutations
in three different type 4 collagen genes (COL4A3, COL4A4 and COL4A5) have been identified. These collagens are found in the basilar
membrane, parts of the spiral ligament, and stria vascularis. Although the
mechanism of hearing loss is not known, it is suggested that the loss of
integrity of the basement membrane might affect adhesion of the tectorial membrane. Also in the glomerulus there is focal
thinning and thickening with eventual basement membrane splitting.
Branchial-oto-renal
syndrome
It is an
autosomal dominant disorder. The main
clinical features include branchial derived anomalies, otologic anomalies, and
renal malformation. The hearing loss
found in BOR is highly variable. The loss can be sensorineural, conductive or
mixed. It can be stable or progressive and the severity can range from
mild to profound. Ear pits are found in
about 80% of the BOR cases. Of those
persons with ear pits, some have only one while others have one in front of
each ear. Some individuals have deformed outer-ear(s), middle-ear(s), and/or
inner-ear(s). About 60% of the BOR cases
have branchial cysts or fistulas which are small holes located on the front,
external lower third of the neck. People
with branchial cysts or fistulas usually have two (one on each side); however,
some only have one. Because they often become infected, branchial cysts or
fistulas are often surgically removed. Kidney
anomalies are found in about 15% of those with BOR. Most of the anomalies have
minimal clinical significance and consists of minor changes in the anatomy of
the kidney or urine collection system. Kidney function is normal in these
individuals. More severe kidney anomalies have been reported. This range
from small, normal functioning kidneys all the way to the kidneys (one or both)
being absent. Three of the less common
symptoms associated with BOR are ear tags, blocked tear ducts, and short
palate.
Branchio-oto-renal syndrome is caused by mutations in EYA1 gene. Expression pattern of
this gene indicated its role in development of the inner ear and kidney. EYA1 homozygous knockout mice
lack ears and kidneys because of apoptotic regression of the organ
primordial.
Jervell and Lange-Nielsen syndrome
It
is an autosomal recessive disorder.
Persons affected by this syndrome have prolongation of the QT interval,
torsade de pointe arrhythmias (turning of the points, in reference to the
apparent alternating positive and negative QRS complexes), sudden syncopal
episodes, and severe-to-profound sensorineural hearing loss.
Two
genes, KVLQT1 and KCNE1, have been
identified. Little is known about the
function of these genes. KVLQT1 is expressed in the stria vascularis of mouse inner ear. Within the inner ear, endolymph homeostasis
is controlled in part by the delayed rectifier potassium channel. This channel
is formed by proteins encoded by the KVLQT1 and KCNE1 genes. Heterozygotes of KVLQT1 have Romano-Ward syndrome, which unlike JLN syndrome, does not include
severe-to-profound hearing loss in the phenotype.
Norrie syndrome
It is X-linked inheritance. Classic features include specific ocular
symptoms (pseudotumor of the retina, retinal hyperplasia, hypoplasia and
necrosis of the inner layer of the retina, cataracts, and phthisis bulbi),
progressive sensorineural hearing loss, and mental disturbance, although less
than one-half of patients are hearing impaired or mentally retarded.
NDP gene has been identified in association with this disease. It encodes for norrin, a protein that has
homologies at the C-terminus to a group of proteins including mucins. The exact mechanism of hearing loss remains
to be determined. It has been suggested
that norrin protein regulates vascularization of the cochlea and retina.
Pendred syndrome
Pendred syndrome is the most common
syndromal form of deafness, accounting for about 4-10% of cases. It is an autosomal recessive disorder and
represents with goiter and sensorineural hearing loss. Usually the goiter is
clinically evident at approximately 8 years of age, but adult onset has also
been noted. Patients are usually
euthyroid but can be hypothyroid. A
positive potassium perchlorate discharge test may be helpful in identifying an
organification defect, the defective organic binding of iodine in the thyroid
gland. But the test is nonspecific and
its sensitivity is unknown. Hearing loss
is usually congenital, bilateral, severe to profound, and sloping in the higher
frequencies. It may be fluctuating or
progressive. Variable vestibular
dysfunction has been exhibited by the patients.
Enlargement of the vestibular aqueducts and the endolymphatic sac and
duct are found in nearly all patients.
An incomplete partition of the cochlear may be present and the vestibule
may be enlarged.
Mutations of the gene PDS on
chromosome 7q31 account for most cases of Pendred syndrome. Mutations in this gene can also be found in
nonsyndromic deafness DFNB4 and many cases of enlarged vestibular aqueduct
syndrome. The PDS gene encodes
pendrin, an anion transporter found in the inner ear, thyroid, and kidney. It possibly plays a role in endolymphatic
fluid resorption.
A PDS knockout mouse was generated in
2001 by
Stickler syndrome
It
is an autosomal dominant disease. Three
phenotypes have been identified. Classic
features of this syndrome include progressive myopia beginning in the first
decade of life and resulting in retinal detachment and blindness, vitreoretinal
degeneration, premature joint degeneration with abnormal epiphyseal
development, midface hypoplasia, and irregularities of the vertebral bodies,
cleft palate deformity and variable sensorineural hearing loss.
It is caused by mutations in COL2A1, COL11A2, or COL11A1. The classic phenotype
is associated with mutations in COL2A1, a fibrillar collagen that
is arrayed in quarter-staggered fashion to form fibers similar to those of
COLI. Mutations in COL11A2 cause STL3, a disease characterized by the typical facial features of
STL1 in combination with hearing impairment. Cleft palate and mild arthropathy also
occur, however ocular signs are absent.
Treacher Collins syndrome
Treacher
Collins syndrome is a disorder of craniofacial development. It is autosomal
dominant inheritance with variable expression.
The features include slanting of the eyes with inferior displacement of
the lateral canthi with respect to the medial canthi, coloboma of the lower lids,
micrognathia, microtia and other deformity of the ears, hypoplastic zygomatic
arches, and macrostomia. Conductive hearing loss and cleft palate are often
present.
TCOF1
gene was identified. It has suggested
that TCOF1 plays a role in nucleolar-cytoplasmic transport. All of the mutations observed resulted in
introduction of premature termination codons into the reading frame and cause premature
termination of the protein product.
Usher syndrome
It is named for Charles Usher (1914), a British ophthalmologist who emphasized their hereditary nature. It is an autosomal recessive disorder. It is characterized y hearing loss and retinitis pigmentosa. Clinically three different types can be distinguished. They are distinguished based on the severity or progression of the hearing loss and extent of the vestibular system involvement. Type 1 patients have congenital profound congenital deafness, absent vestibular response and the onset of retinitis pigmentosa is in the first decade of life. Type 2 patients have normal vestibular response. Type 3 patients have progressive hearing loss, variable vestibular response and variable onset of retinitis pigmentosa.
A total of
11 loci and 6 genes have been identified in Usher syndrome. Among these, MYO7A, which belongs to
the family of unconventional myosins, encode myosin 7A. It represents a unique molecular motor for
hair cells. In the mutant mice, the
organization of stereocilia bundles is disrupted, impairing the function of
hair cells. CDH23 gene encodes
cadherin 23, which is an adhesion molecule maybe important for crosslinking of
stereocilia. It may also be involved in
maintaining the ionic composition of the endolymph. Studies have suggested that myosin 7A,
cadherin 23, along with another protein harmonin, which in coded by USH1c
gene, form a transient functional complex in stereocilia.
Waardenburg Syndrome
The disease was named for Petrus Johannes Waardenburg, a Dutch ophthalmologist (1886-1979) who was the first to notice that people with two different colored eyes frequently had hearing problems. The clinical features usually include dystopia canthorum, meaning the lateral displacement of the inner canthus of the eyes to give an appearance of a widened nasal bridge, pigmentory abnormalities of the skin, iris, and hair, and sensorineural hearing loss. There is a great deal of variation in the hearing loss. Some of the affected persons escape deafness. There are four subtypes of Waardenburg syndrome have been described. Type 1 typically shows wide confluent eyebrow, high broad nasal root, heterochromia irides, brilliant blue eyes, premature gray of hair, eyelashes, or eyebrows, white forelock, and vestibular dysfunction. Type 2 is like type 1 but without dystopia canthorum. The penetrance of hearing loss is slightly higher in type 2 than type1. Type 3 is also called Klein-Waardenburg syndrome. It has type 1 clinical features and hypoplastic muscles and contractures of the upper limbs. Type 4 is also called Shal-Waardenburg syndrome. It has type 2 clinical features and Hirschsprung’s disease.
Five genes
on five chromosomes have been identified.
PAX3 gene mutations have been indicated to be associated with
type 1 and type3 phenotypes. PAX3 is a
DNA-binding protein that is important in determining the fate of neural crest
cells in the developing nervous system.
Type 2 has been linked to MITF gene mutation. Three genes have been associated wit type 4
phenotypes. They are EDN3, EDNRB,
and SOX10. In vitro studies of EDN3
showed a stimulation of proliferation and melanogenesis of neural crest cells. EDNRB is postulated to play an
essential role in the development of the two neural crest-derived cell
lineages, epidermal melanocytes and enteric neurons. SOX10 belongs to the family of
transcription factors that bind DNA and regulate its transcription. Interaction of these three genes has been
suggested. The genetics of Waardenburg
syndrome highlight the principle of genetic heterogeneity.
Nonsyndromic hearing loss
According to the Hereditary Hearing Loss homepage (www.uia.ac.be/dnalab/hhh/
), 80 loci for nonsyndromic hearing loss have been mapped to the human
genome. And 30 genes have been
identified. Based on the type of gene
product, these genes can be categorized into several groups. 1) channel and gap junction components, 2) myosin
and other cytoskeletal proteins, 3) transcription factors, 4) extracellular
matrix proteins, 5) unknown function genes.
There
are autosomal dominant, autosomal recessive and X-linked forms of nonsyndromic
hearing loss. In general, recessive
inheritance shows prelingual onset of hearing loss. And the severity is severe to profound with
all frequencies affected. In autosomal
dominant forms, the phenotype is less severe.
The onset is usually postlingual.
The severity is ranging from moderate to severe. Hearing loss is seen in middle, high, or all
frequencies with only three loci having hearing loss in the low frequency
range.
Genes for homeostasis
Maintaining ion homeostasis within the cochlear duct, especially the
high potassium concentration in the endolymph, is of extreme importance for
signal transduction involved in the hearing process. Potassium recycling pathway is postulated to
start with an efflux of potassium from the outer hair cells through potassium
channel. Through gap junctions between
the supporting cells, the ions migrate to the stria vascularis, for where they
are secreted into the endolymph.
Four connexins have been implicated: connexin 26 (GJB2), connexin 31 (GJB3), connexin 30 (GJB6), and connexin 43 (GJA1). Connexins belong to a family of gap junction
proteins responsible for the intercellular transport of ions, metabolites, and
second messengers. GJB2 is the first nonsyndromic sensorineural deafness gene to be
identified. It is estimated that
mutations of GJB2 accounts for 50% of recessive nonsyndromic
hearing loss. GJB2 encodes connexin 26. Animal
studies to examine the role of connexins in the cochlea have been undertaken
only for this protein. It is expressed
in stria vascularis, basement membrane, limbus, and spiral prominence of
cochlea. Rat immunohistochemical finding
suggest that it plays a role in recycling of potassium ions back to the
endolymph of the cochlear duct after stimulation of the sensory hair cells. 80 recessive and 6 dominant mutations have
been found in GJB2. One
mutation, 35delG (one guanosine residue deletion from nucleotide position 35),
is very frequent in Caucasian population.
This mutation results in shifting of the reading frame and protein
truncation. Because of the high
prevalence of this mutation in Western countries and the small size of the GJb2 gene, diagnostic testing is available.
KCNQ4 is a component of a potassium channel.
It is though to be involved in the potassium recycling pathway as
well. SLC26A4 encodes an anion
transporter. This mutation gives rise to
a broad spectrum of clinical symptoms: from nonsyndromic SNHL to hearing loss
with enlarged vestibular aqueduct to full-blown Pendred syndrome with thyroid
goiter.
Transcription factors
Four transcription factor genes have been identified: POU3F4, POU4F3, EYA4, and TFCP2L3. POU3F4 is responsible for
X-lined mixed hearing loss. The
conductive hearing loss is from stapes fixation. These patients suffer from an increased
perilymphatic pressure causing the typical “gusher” that appears during stapes
footplate surgery. POU4F3 is associated with autosomal dominant hearing loss. Its knockout mice fail to develop hair cells
with subsequent loss of spiral and vestibular ganglia. No gross morphological changes were seen in
Pou3f4 knockout mice, but ultrastructural alterations wee found in the spiral
ligament fibrocytes. Both EYA 4 and TFCP2L3 cause autosomal dominant hearing loss.
Cytoskeleton
proteins
Maintaining
the highly organized and specialized structures like actin-rich stereocilia of
the sensory hair cells is very important for the processes of hearing and
balance. Among the cytoskeletal
components involved in nonsyndromic hearing loss are myosins, otoferlin, actin-polymerization
protein, harmonin, and cadherin. Four
unconventional myosins genes (MYO3A, MYO6, MYO7A, MYO15) and one conventional
myosin gene MYH9 have been identified. Myosins are molecular motor proteins that
bind to actin and that hydrolyze ATP to generate the force to move across actin
filaments. Unconventional myosins move
macromolecules along actin filaments.
They are important for the structural integrity of the stereocilia. All the unconventional myosin mouse models
display the vestibular dysfunction.
Otoferlin
acts in calcium triggered synaptic vesicle trafficking. It is encoded by OTOF. Recently it has been reported
to account for 4.4% of recessive nonsyndromic hearing loss negative for GJB 2 mutations in Spanish population.
If this finding is confirmed in other population, it might be one of the
genes with putative diagnostic implications.
Harmonin organizes multiprotein complexes in specific subcellular
domains. They anchor and cluster
transmembrane proteins and recruit signaling molecules. They are also associated with Usher type 1C
disease.
Cadherins are components of adherens junctions and play critical roles
during embryogenesis and organogenesis.
It is encoded by CDH23. In mouse model, the mutations showed
disruption of stereocilia organization during early hair cell
differentiation. It is also associated
with Usher type 1D disease.
Extracellular
matrix components
The
tectorial membrane overlying the hair cells plays a crucial role in the
mechanosensory transduction process. TECTA gene encodes alpha tectorin, a component of the tectorial
membrane. Knockout mice showed
detachment of tectorial membrane from the cochlear epithelium. COL11A2 encode type XI
collagen. The knockout mice have
atypical and disorganized collagen fibrils of the tectorial membrane. COCH protein is ubiquitously
present in the inner ear. It is
expressed in cochlea as well as vestibular organs. COCH mutation exhibits
symptoms of Meniere, including vertigo, tinnitus and a pressure feeling in the
ear.
Mitochondrial Hearing Loss
In addition to nuclear genes some
mitochondrial genes have been associated with genetic hearing loss. As
mitochondria have a crucial function in nearly every cell, it is not unexpected
that mitochondrial DNA mutations mainly cause multisystemic diseases, of which
hearing impairment is often an additional symptom. Two different mitochondrial
genes are involved. First, the 1555A->G mutation in the 12S rRNA gene leads
to aminoglycoside-induced hearing loss and nonsyndromic hearing loss. The second gene is the tRNASer(UCN) gene, in
which four different mutations are known to cause nonsyndromic hearing
impairment.
Evaluation
A
complete history should include prenatal, perinatal, postnatal, and family
history. Especially in family history,
it is important to inquire hearing loss in the first and second degree
relatives, especially if the loss started before age 30. Consanguinity or common origin form ethnically
isolated areas should increase suspicion of hereditary hearing loss. If there are a number of family members with
hearing loss, constructing a pedigree is important.
Physical exam should focus on looking for features associated with
congenital infection or syndromic hearing loss.
Note hair color, the presence of a white forelock, facial shape, and
skull shape. On eye examination, one
should note the color of the iris, position of the medial and lateral canthum,
intercanthal distance, cataracts, and any retinal findings. Examine the ear for preauricular pit, skin
tags, shape and size of the pinna, or abnormality of EAC or TM. Examine the neck for branchial anomalies and
thyroid enlargement and oral cavity for cleft.
Thorough inspection of skin for areas of hyper or hypopigmentation and
café-au-lait spots. Do a complete
neurological exam including gait and balance to evaluate vestibular
function.
In
addition to audiogram, lab test should be ordered based on the history and
physical exam. All children with hearing
loss should have a urinalysis to assess for renal dysfunction. Other tests should be ordered as appropriate,
for example, thyroid function test and EKG in suspected Pendred syndrome and
Jervell and Lange-Neilsen syndrome.
Genetic counseling is an important part of evaluation. The counseling team usually consists of
clinical/medical geneticist, genetic counselor, social worker, and
psychologists. The risk and benefit of
genetic testing should be explained to the family and consent should be obtained
before genetic testing. Three genetic tests
are available: GJB2, SLC26A4, and EYA1. Knowing the genetic cause of a person’s hearing loss can lead to
improved decision about treatment and management. Genetic information can help predict whether
the hearing loss will remain the same or whether it will worsen over time. Knowledge of the genetic cause is also
helpful in determining what kind of damage has happened to the hearing system
to cause the deafness. This is important
because how the inner ear is damaged may affect whether a cochlear implant, or
other hearing device, may help a patient.
In addition, genetic testing can help determine if problems besides
hearing loss may be present or may develop in the future. Genetic testing can also provide a deaf
individual or the parents of deaf child information when making reproductive
choices.
Since the identification of the first deafness gene in 1995 a
respectable number of genes have been identified. As a consequence, the
molecular knowledge of the processes responsible for hearing and balance and of
the pathological mechanisms leading to hearing loss is expected to increase
tremendously. But there is still a long way to go. Many genes remain to be
identified. Moreover, the elucidation of the exact function of genes for which only
a putative function was proposed, and of genes with an unknown function remains
a great challenge.
Bibliography: