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Association of Clinical Features With Mutation of TECTA in a Family With Autosomal Dominant Hearing Loss
Satoshi Iwasaki, MD;
Daisuke Harada, MD;
Shin-ichi Usami, MD;
Mitsuyoshi Nagura, MD;
Tamotsu Takeshita, MD;
Tomoyuki Hoshino, MD
Arch Otolaryngol Head Neck Surg. 2002;128:913-917.
ABSTRACT
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Background The TECTA gene, which encodes  -tectorin,
has recently been cloned. -Tectorin is a major component of the noncollagenous
matrix of the tectorial membrane. Nonsyndromic hearing impairment caused by TECTA mutations has been reported in Austrian, Belgian,
Swedish, French, and Lebanese families. The phenotypes and genotypes were
different among these families.
Materials and Methods Our study family displayed autosomal dominant hearing impairment through
3 generations. We sequenced the coding exons of the TECTA gene in 4 affected individuals, and we report the clinical features
in a Japanese family with nonsyndromic hearing impairment and a mutation in
the TECTA gene.
Results The 5-frequency average of 250, 500, 1000, 2000, and 4000 Hz in 4 affected
individuals was 42.2 ± 3.7 (mean ± SD) dB in the right ear and
42.3 ± 4.5 dB in the left ear. The mean age at onset of hearing impairment
was 5 years. The progression of hearing impairment was not confirmed for a
15-year period, from the age of 6 to 21 years, in 1 affected member. The 4
patients had a G A missense mutation at nucleotide 6063 in exon 20. This
mutation replaces arginine at residue 2021 with histidine (R2021H).
Conclusions All 4 affected members showed symmetrical and stable bilateral mild
to moderate hearing impairment in the midfrequencies. The mean threshold level
of 2000 Hz was the worst among the 5 frequencies. All the affected members
had normal vestibular function. The mutation in the TECTA gene, localized in the zona pellucida domain, was detected in all
4 affected individuals. The localization of the mutation in the different
modules of the protein may have caused the different clinical features.
INTRODUCTION
THERE HAS been tremendous progress in the research of the genetic basis
of deafness. It had always been assumed that single-gene defects were responsible
for hearing impairment, but many different genes causing deafness, which probably
account for more than 50% of the cases of childhood deafness, have recently
been reported.1 So far, 70 loci involved in
nonsyndromic deafness have also been reported.2
The tectorial membrane is an extracellular gellike matrix leaf that
attaches to the tallest row of the stereociliary bundles of the outer hair
cells. The displacement of the tectorial membrane stimulates the outer hair
cells, which open the transduction channels and lead to hair cell depolarization.
The ultrastructural defects of the tectorial membrane are caused by mutations
in 3 different points of genes, namely encoding -tectorin (TECTA),3 collagen 11-2
(COL11A2),4 and otogelin
(Otog),5 which lead
to human hearing impairment.6 The tectorial
membrane contains collagenase-sensitive and -insensitive proteins. The major
components of the noncollagenous matrix are -tectorin and ß-tectorin,
which interact with each other.2
The TECTA gene has recently been cloned and
shown to be associated with nonsyndromic hearing impairment.3
It encodes a protein of 2155 amino acids, 95% of which are identical to mouse -tectorin,
which has an aminoterminal hydrophobic signal sequence for translocation across
the membrane and a carboxy-terminal hydrophobic region characteristic of precursors
for glycosylphosphatidylinositol-linked membrane-bound proteins.7
An alteration in -tectorin is likely to disrupt the structure of this
matrix. DFNA8,8 DFNA12,9 and DFNB2110 loci are mapped on chromosome
11q11 and are all segregating alleles of TECTA. Nonsyndromic hearing impairment caused by TECTA mutations has been reported in Austrian,3 Belgian,3 Swedish,12 French,13 and Lebanese10 families. The phenotypes and genotypes were different
among these families. In this study, we describe the clinical features in
a Japanese family with autosomal dominant nonsyndromic hearing impairment
and present a mutation analysis of the TECTA gene.
SUBJECTS AND METHODS
CLINICAL DIAGNOSIS
A family pedigree was constructed at Hamamatsu University Hospital,
Hamamatsu City, Japan (Figure 1).
Otoscopic and audiometric examinations were performed on all cooperative family
members. Blood samples from the family members were obtained after informed
consent was granted. Pure-tone audiometry was performed with air conduction
at 125, 250, 500, 1000, 2000, 4000, and 8000 Hz and with bone conduction at
250, 500, 1000, 2000, and 4000 Hz. Audiograms were available for 4 members
(III:2, III:3, II:2, and I:7) of the pedigree. A speech discrimination test,
otoacoustic emissions screening (Capella; GN Otometrics, Tokyo, Japan), a
caloric test, and computed tomography were also performed. For 1 member (II:2),
we can chart the hearing impairment via audiometric examinations over a long
term. His hearing impairment was detected during an examination in primary
school when he was 6 years old, and he experienced head trauma while playing
a sport at the age of 10 years. Congenital aural fistula of the right ear
was confirmed in patient III:3, and her hearing impairment was noticed by
her parents when she was 4 years old. Patient II:2 was diagnosed as having
hypothyroidism (Hashimoto disease). Patient I:5 had a noise-induced hearing
impairment. A hearing aid was used by patients I:4 and I:6. None of the 4
affected family members, all of whom underwent audiometric testing, had complained
of tinnitus or vertigo.
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Figure 1. A Japanese pedigree with autosomal
dominant hearing loss. Four affected family members (II:2, II:7, III:2, and
III:3) were identified with TECTA mutation. Member
III:3 had a congenital aural fistula in the right ear. Hypothyroidism (Hashimoto
disease) was diagnosed in member II:2. Member I:5 had worked in a noisy environment.
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MUTATION ANALYSIS
Intronic polymerase chain reaction (PCR) amplification primers flanking
each exon3 were used to detect mutations. Exons
1-20 of TECTA were amplified from genomic DNA samples
by PCR. A 5-minute denaturation at 95° was followed by 35 three-step cycles
(95° for 30 seconds, 55° for 1 minute, and 72° for 1 minute),
followed by 72° for 10 minutes, and ending with a holding period at 4°
in a thermal cycler (Perkin-Elmer Corp, Norwalk, Conn). The PCR products were
directly sequenced after removal of unincorporated dinucleotide triphosphates
and primers by incubation at 37° for 30 minutes with 50-to 100-ng PCR
product with 0.1 µL of exonuclease I (Amersham Life Science, Cleveland,
Ohio) and 1 µL of shrimp alkaline phosphatase (Amersham Life Science).
The enzymes were heat inactivated at 80° for 15 minutes. An aliquot of
6 pmol of either the forward or the reverse primer was used in standard cycle
sequencing reactions and run on a sequencer. DNA samples from 96 unrelated
Japanese, who had normal hearing, were used as controls.
RESULTS
Audiograms of the 4 affected members are shown in Figure 2. They demonstrated bilateral mild to moderate, symmetrical,
and stable sensorineural hearing impairment in the midfrequencies. The mean
± SD level of hearing impairment at 250, 500, 1000, 2000, and 4000
Hz was 42.2 ± 3.7 dB (range, 38-47dB) in the right ear and 42.3 ±
4.5 dB (range, 36-47dB) in the left ear. The mean ± SD level at each
frequency was 22.6 ± 5.5 dB (250 Hz), 32.5 ± 14.4 dB (500 Hz),
51.3 ± 14.3 dB (1000 Hz), 66.3 ± 12.5dB (2000 Hz), and 35 ±
20.0 dB (4000 Hz) in the right ear and 26.3 ± 7.5 dB (250 Hz), 36.3
± 8.5 dB (500 Hz), 48.8 ± 7.5 dB (1000 Hz), 57.5 ± 15.5
dB (2000 Hz), and 42.5 ± 17.0 dB (4000 Hz) in the left ear. The history
of the progression of hearing impairment charted by audiometry over 15 years
(from age 6-21 years) in patient III:2 is shown in Figure 3. The mean level of maximum speech discrimination was 95%
at the stimulus level of 70 dB. The responses on the distortion-product otoacoustic
emissions and the transient evoked otoacoustic emissions were decreased, which
indicated that the current hearing impairment was caused by inner ear dysfunction.
All the affected members had normal vestibular function. Abnormality of the
inner ear was not found with computed tomography.
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Figure 2. Representation of audiograms for
the 4 affected family members (II:2, II:7, III:2, and III:3) at the age of
7 years (III:3), 18 years (III:2), 33 years (II:7), and 42 years (II:2). The
mean ± SD level of hearing loss at 5 frequencies was 42.2 ±
3.7 dB (right ear) and 42.3 ± 4.5 dB (left ear), and the maximum level
of hearing loss was 2000 Hz (57.5 ± 15.5 dB).
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Figure 3. Long-term follow-up on audiometric
tests in an affected member (III:2). The history over 15 years, from the age
of 6 years to 21 years, of hearing impairment at 7 frequencies and the mean
level of hearing loss in the right ear are shown.
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The GA missense mutation at nucleotide 6063 in exon 20 in the TECTA gene was detected in all 4 affected members (Figure 4). This mutation replaces arginine
at residue 2021 with histidine (R2021H). All 4 affected members were heterozygous
for this mutation. The present mutation was not found in any of the samples
from Japanese controls.
COMMENT
A Japanese family with nonsyndromic autosomal dominant hearing loss
was investigated. The hearing loss was bilateral and symmetrical, and there
was inner ear dysfunction. Stable, moderate, and midfrequency hearing loss
was detected on auditory examinations of all 4 affected members at a mean
age of 5 years. Histories of delayed speech development and distortion of
utterance suggested a prelingual onset of hearing impairment. The mean ±
SD level of hearing impairment was 42.2 ± 3.7 dB (right ear) and 42.3
± 4.5dB (left ear). The mean threshold level of 2000 Hz was the worst
among the 5 frequencies (250-8000 Hz). We were able to follow the history
of hearing impairment with audiometry for 15 years (from age 6-21 years) in
1 affected member. The hearing impairment did not change during that period.
The head trauma of 1 affected member did not induce a progression of hearing
impairment.
Mutation of the TECTA gene has been identified
in Belgian,3 Austrian,3
French,13 Swedish,12
and Lebanese10 families with nonsyndromic hearing
loss. The characteristics of nonsyndromic hearing loss in these families were
classified into 2 phenotypes. Nonsyndromic autosomal dominant hearing loss
was found in the Belgian,3, 9, 14
Austrian,3, 15 French,13 and Swedish,12, 16
families in addition to the current family. Nonsyndromic autosomal recessive
hearing loss was found in the Lebanese family.10
Mild to severe and progressive hearing loss in the high frequencies was reported
in the French and Swedish autosomal dominant families. The onset of hearing
impairment was different between the French and Swedish families. Although
the hearing impairment in the Swedish family was postlingual, with a mean
age at onset of 14 years old, hearing impairment in the French family was
detected before the age of 6 years, and a prelingual onset has been suggested
because of a history of delayed speech development. Mild to moderately severe,
prelingual, and stable midfrequency hearing loss was reported in the Belgian
and Austrian autosomal dominant families. The current audiological features
are similar to those in the Austrian and Belgian families (Table 1). The autosomal recessive hearing loss in the Lebanese family
was severe to profound (70-110 dB) and prelingual in all frequencies. The
hearing loss in an autosomal recessive family is always characterized by profound,
prelingual onset and a stationary pattern. In contrast, most autosomal dominant
families have postlingual and progressive hearing loss.8
However, the human tectorial membrane is formed between the 12th and 20th
weeks of embryonic development.3 -Tectorin
and ß-tectorin, which are major components of the noncollagenous matrix
of the tectorial membrane, are only expressed transiently during cochlear
development in the mice.3 Referring to these
features, the characteristics of nonsyndromic hearing loss caused by mutation
of TECTA seem to be prelingual onset and a stationary
pattern.
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Association of Clinical Features and Genotype With TECTA Mutations*
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There was no history of vertigo or dizziness in the present family or
in the previously described families. A caloric test as a vestibular examination
also revealed normal function. However, some affected members of the French
family were late to start walking, which can be explained by a deficit of -tectorin
in the vestibular organ. -Tectorin is expressed in the 2-day mouse
utricle and saccule.7
The TECTA gene is composed of 3 distinct modules:
entactin G1 domain, zonadhesin domain (with von Willebrand factor type D repeat),
and zona pellucida domain.12 The mutations
found in the Belgian, Austrian, and present families were localized in the
zona pellucida domain. A missense mutation at nucleotide 5876 in exon 18 replaced
tyrosine at residue 1870 with cysteine (Y1870C) in the Austrian family.3 The Belgian family demonstrated 2 mutations in exon
17, which replaced leucine at residue 1820 with phenylalanine (L1820F) and
aspartic acid at residue 1824 with glycine (G1824D).3
The present missense mutation at nucleotide 6063 in exon 20 leads to a substitution
of arginine for histidine at residue 2021 (R2021H) and has been identified
in 4 affected members. The mutation of TECTA in the
zona pellucida domain (residues 1805-2057) may disrupt the interactions between
the different polypeptides of tectorial membrane, and, as a consequence, improper
assembly of the tectorial membrane might cause an inefficient mechanotransduction
process. The mutations found in the French and Swedish families were identified
in the zonadhesin domain of TECTA. This mutation
abolishes the first of the vicinal cysteine present in the D4 von Willebrand
factor type D repeat12 and may cause a change
in the cross-linking of the polypeptide. A missense mutation at nucleotide
4857 in exon 14 replaced the cysteine at residue 1619 with serine (C1619S)
in the French family.13 The mutation found
in the Swedish family resulted in the replacement of cysteine with serine
at residue 1057 (C1057S) in exon 10.12 Although
these mutations were identified heterozygously in the affected members, the
mutation found in the Lebanese family led to the identification of a GA
transition in the donor splice site of intron 9 homozygously in the affected
members, skipping exon 9 and resulting in a stop codon at amino acid position
972.10
The mutations localized in the zona pellucida domain resulted in the
prelingual and stable hearing loss in the midfrequencies in the autosomal
dominant families. The progressive hearing loss in the high frequency was
found in the autosomal dominant family in which the mutation was identified
in the zonadhesin domain. These findings suggest that the localization of
the mutation in the different modules of the protein may result in the different
phenotypes.
AUTHOR INFORMATION
Accepted for publication January 10, 2002.
This work was supported by a grant from the Acute Profound Deafness
Research Committee of the Ministry of Health, Labour, and Welfare of Japan.
We thank all members of the family for their participation in this study.
Corresponding author and reprints: Satoshi Iwasaki, MD, Department
of Otolaryngology, Hamamatsu University School of Medicine, 1-20-1 Handayama,
Hamamatsu City 431-3192, Japan (e-mail: iwasaki{at}hama-med.ac.jp).
From the Department of Otolaryngology, Hamamatsu University School
of Medicine, Hamamatsu City (Drs Iwasaki, Nagura, Takeshita, and Hoshino)
and Shinshu University School of Medicine, Matsumoto City (Drs Harada and
Usami), Japan.
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