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Autosomal Dominant Inherited Hearing Impairment Caused by a Missense Mutation in COL11A2 (DFNA13)
Els M. R. De Leenheer, MD;
Henricus P. M. Kunst, PhD;
Wyman T. McGuirt, MD;
Sai D. Prasad, MD;
Matthew R. Brown, MD;
Patrick L. M. Huygen, PhD;
Richard J. H. Smith, MD;
Cor W. R. J. Cremers, PhD
Arch Otolaryngol Head Neck Surg. 2001;127:13-17.
ABSTRACT
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Objective To analyze the phenotype in a 5-generation DFNA13 family with a missense
mutation in the COL11A2 gene that causes autosomal
dominant, presumably prelingual, nonsyndromic sensorineural hearing impairment.
Design Family study.
Setting University hospital department.
Patients Twenty mutation carriers from a large American kindred.
Methods Cross-sectional analysis using pure-tone threshold measurements at 0.25,
0.5, 1, 2, 4, and 8 kHz. The audiometric configuration was evaluated according
to an existing consensus protocol. The significance of features relating to
audiometric configuration was tested using 1-way analysis of variance. Progression
was evaluated with linear regression analyses of threshold-on-age.
Results Most individuals showed midfrequency (U-shaped) characteristics. The
mean threshold in generations IV and V was 44 dB at 1, 2, and 4 kHz (midfrequencies);
it was 29 dB at the other frequencies (0.25, 0.5, and 8 kHz). There was no
significant progression beyond presbyacusis.
Conclusion The trait in this family can be characterized as autosomal dominant,
nonprogressive, presumably prelingual, midfrequency sensorineural hearing
impairment.
INTRODUCTION
GENETIC linkage techniques have facilitated the identification of genes
essential for normal auditory function. The initial step in this process is
the localization of these genes using classic linkage techniques; since 1992,
38 loci for autosomal dominant nonsyndromic sensorineural hearing loss have
been mapped, and 11 of the relevant genes have been cloned. The different
gene loci for the nonsyndromic forms of hearing impairment have been called
DFN (DeaFNess) and are numbered in chronological order of discovery. Autosomal
dominant loci are referred to as DFNA, autosomal recessive as DFNB, and X-linked
as DFN. An update of these genetic data can be obtained by consulting the
Hereditary Hearing Loss Homepage.1
The identification of these genes, in turn, has prompted studies to
determine whether phenotypic-genotypic correlations exist. It is well known
that different mutations in the same gene can produce a broad spectrum of
phenotypes.2 For example, mutations in the
myosin VIIA gene (MYO7A) cause Usher syndrome type
1B,3 DFNB2,4, 5
and DFNA11,6 and mutations in the Pendred syndrome
gene (PDS) cause Pendred syndrome7
and DFNB4.8 Mutations in the COL11A2 gene also cause syndromic and nonsyndromic hearing loss.
Two DFNA13 kindreds, one American9 and
the other Dutch, recently were shown to have missense mutations in the COL11A2 gene.10 The COL11A2 gene encodes the  2(XI) chain
of type XI collagen. Type XI collagen is a minor fibrillar component of cartilage
collagen. Mice with a targeted disruption of the col11a2 gene have hearing loss and, by electron microscopy, loss of organization
of the collagen fibrils in the tectorial membrane.10
A mutation in the COL11A2 gene was also identified
as the cause of hearing impairment in persons with Stickler syndrome type
2 (STL2).11, 12 This autosomal
dominant syndrome is characterized by hearing impairment, midface hypoplasia,
and arthropathy, but in contrast to the classic form of Stickler syndrome,
there is no ocular involvement, reflecting absence of COL11A2 gene expression in the vitreous.13
Hearing loss in patients with STL2 is reported mostly mild to moderate, sensorineural
or mixed.11, 14, 15
An autosomal recessive syndrome, otospondylomegaepiphyseal dysplasia, which
includes otospondylofacial dysplasia, bone dysplasia, midface hypoplasia,
and deafness, also can be caused by COL11A2 gene
mutations.12, 16
To establish whether phenotypic-genotypic correlations exist, it is
imperative to describe phenotypes, based on their genotypes, as thoroughly
as possible. We present herein a detailed analysis of the clinical data of
the American DFNA13 family, and relate these phenotype findings to the other COL11A2-linked disorders.
PATIENTS AND METHODS
An American family spanning 5 generations and comprising 67 members
alive (Figure 1)10
showed autosomal dominant sensorineural hearing impairment, presumably affecting
38 persons (15 by history). Forty persons underwent general and otorhinolaryngological
examinations, including audiometry. Individual V-13 was excluded from the
study because the reliability of the hearing test was questioned. Genetic
linkage analysis was performed and the hearing loss segregated with markers
on chromosome 6p21-p22; this locus was designated DFNA13.9
Recently, a missense mutation in the COL11A2 gene was reported
in this family.10 Two phenocopies (individuals
III-8 and III-17) were identified. They had hearing loss confirmed by audiograms,
but lacked the gene mutation; their audiograms could not be distinguished
from those in the mutation carriers.
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Figure 1. Pedigree of the American DFNA13
family. Roman numerals indicate different generations; squares, men; circles,
women; solid symbols, hearing impairment; +, gene carriers; and a, audiogram
available. All individuals in generations I and II (except II-2) and person
III-13 are deceased.
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The present analysis of the hearing phenotype includes only those persons
carrying the COL11A2 gene missense mutation from whom at least
one audiogram had been obtained (n = 20). Corrections were made for presbyacusis
by subtracting the ISO 7029 median norm (50th percentile [P50]) threshold
for presbyacusis17 from each person's threshold,
according to that person's age and sex. For persons older than 70 years, the
P50 values for age 70 years (the maximum age for which normative data are
available) were used. Audiograms (air conduction threshold, in decibels, hearing
level) were recorded in a sound-shielded room following common clinical standards.
Audiometric configuration was classified according to the criteria formulated
by the European Work Group on Genetics of Hearing Impairment.18 Midfrequency hearing impairment (a U-shaped audiogram) is defined as
follows: a 15-dB difference or greater between the poorest thresholds in the
midfrequencies (>0.5 to 2 kHz) and those at higher and lower frequencies.
The low-frequency ascending pattern is defined as a difference
of 15 dB or greater between the thresholds at the poorer low frequencies and
the higher frequencies. A flat audiogram is defined as a difference
of less than 15 dB from 0.25 to 8 kHz. High-frequency hearing
impairment is subdivided into gently and steeply sloping configurations. The
former type is defined as a 15- to 29-dB difference between the mean of 0.5
and 1 kHz and the mean of 4 and 8 kHz, while the latter implies a 30-dB difference
or greater between the described frequencies.
One-way analysis of variance and regression analyses were performed
on cross-sectional threshold-on-age data (last-visit audiogram) using a commercial
program (Prism, PC version 2.01; GraphPad, San Diego, Calif). To evaluate
whether significant progression (slope >0) occurred, linear regression analysis
was performed using only the raw threshold-on-age data in generations IV and
V (age range, 11-48 years); the affected persons in generation III (age range,
67-75 years) were substantially older. By excluding generation III, the potentially
confounding effects of presbyacusis were avoided. All threshold-on-age data
were used in an attempt to fit parabolic curves, similar to the fits on which
the ISO 7029 norms17 are based: Y=
offset + [a(X- 18)2], where Y is the binaural mean air conduction threshold (measured in decibels), X is age (in years), and a is acceleration of hearing
deterioration (measured as decibels times years negatively squared). Chauvenet
criterion was used to detect any outlying values, ie, data points pertaining
to excessively large regression residues.19
We also determined whether each ISO 7029 value for a17 was within the calculated 95% confidence interval
for a (t distribution).
RESULTS
All 20 persons examined and known to carry the COL11A2 gene mutation showed sensorineural hearing impairment (Figure 2A-T). The individuals are given in ascending order of age
at the last visit. Classification of audiometric configuration was based on
the original data (ie, without presbyacusis correction). Of the 40 ears, 17
showed a U-shaped audiogram (Figure 2A,
B, F, G, J, and M [right and left ears] and D, H, I, N, and O [left ear only]).
Other audiometric types included a flat configuration in 6 ears (Figure 2L, R, and T [right and left ears]),
gently downsloping in 3 ears (Figure 2C,
H, and K [right ear]), and steeply downsloping in 4 ears (Figure 2Q and S [right and left ears]). The latter persons had a
history of significant noise exposure. Low-frequency ascending curves were
found in 3 ears (Figure 2E [right
and left ears] and N [right ear only]), and in 7 ears (Figure 2C and K [left ear only], D, I, and O [right ear only], and
P [right and left ears]) the audiometric configuration could not be classified.
The ears in Figure 2O (right ear
only) and P (right and left ears) showed a threshold curve that gently sloped
from the low frequencies to a dip at 4 kHz but ascended at 8 kHz. In the last
3 individuals, there was no history of noise exposure. In 4 ears (Figure 2C and K [left ear] and D and I [right
ear]), although the configuration was gently downsloping, the degree of slope
did not meet the classification criterion. In some persons (ie, the oldest
patients), presbyacusis correction changed the audiometric configuration.
In Figure 2Q-S, the audiogram could
no longer be classified. In Figure 2R,
the audiometric curve was similar to those seen in Figure 2O (right ear) and P (right and left ears), but with a dip
at 2 kHz. After correction for presbyacusis, Figure 2T fits the description of a low-frequency ascending curve.
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Figure 2. Air conduction threshold (continuous
lines and open circles), together with the threshold minus the 50th percentile
of presbyacusis (dashed lines and solid circles) for that person's age and
sex in 20 affected persons. A, Individual V-2, an 11-year-old boy. B, Individual
V-1, an 11-year-old boy. C, Individual V-4, an 11-year-old boy. D, Individual
V-12, a 14-year-old boy. E, Individual V-6, a 17-year-old girl. F, Individual
IV-18, a 28-year-old woman. G, Individual IV-12, a 33-year-old man. H, Individual
IV-17, a 33-year-old man. I, Individual IV-11, a 36-year-old man. J, Individual
IV-10, a 38-year-old woman. K, Individual IV-15, a 39-year-old man. L, Individual
IV-13, a 40-year-old man. M, Individual IV-8, a 42-year-old man. N, Individual
IV-4, a 42-year-old man. O, Individual IV-26, a 44-year-old woman. P, Individual
IV-2, a 48-year-old woman. Q, Individual III-6, a 67-year-old man. R, Individual
III-16, a 73-year-old woman. S, Individual III-3, a 73-year-old man. T, Individual
III-1, a 75-year-old man. For each set, the left panel indicates the right
ear; and the right panel, the left ear.
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While the audiometric configuration was variable, the predominant type
was identified as U-shaped (42.5% [17 of 40 ears]), even including data corrected
for presbyacusis. The "mean audiogram" also showed a U-shaped configuration
(Figure 3); the thresholds at 0.25
to 4 kHz differed significantly from the one at 0 kHz. The mean thresholds
at 0.25, 0.5, and 8 kHz appeared fairly similar (mean, about 29 dB) and so
did the mean thresholds at the frequencies from 1 to 4 kHz (mean, about 44
dB). Thus, the difference between these grouped frequencies (15 dB) complied
with the definition of a U-shaped configuration. These (raw) data (Figure 3) cover only generations IV and V
to avoid any major influence of presbyacusis.
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Figure 3. The "mean audiogram" ±
1 SD based on the raw thresholds of the analyzed cases in generations IV and
V.
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Analysis of variance disclosed significant intragenerational and thus
age-related differences in threshold (raw data) for a given frequency (data
not shown). Linear regression analysis was performed on the raw threshold-on-age
data in the combined generations IV and V. Only the 0.5-kHz frequency showed
mild, but significant, progression (0.3 dB/y), which vanished following presbyacusis
correction (data not shown).
The age-corrected threshold shows ascending characteristics in generation
III (Figure 2Q-T), which would have
been even stronger if we had been able to use appropriate P50 values for the
persons older than 70 years (Figure 2R-T).
We attempted to circumvent this limitation by fitting ISO 7029 presbyacusis
parabolas to the threshold data, as described in the "Patients and Methods"
section (Figure 4A-F). The fitted
offset values were included in the parabolic fit according to the usual median
(P50) presbyacusis norms. The curves thus obtained were used to compare the
apparent age-related progression with the expected progression in presbyacusis.
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Figure 4. Analysis of progression in threshold
(circles indicate the raw binaural mean threshold for air conduction) with
advancing age. A, 0.25 kHz; B, 0.5 kHz; C, 1 kHz; D, 2 kHz; E, 4 kHz; and
F, 8 kHz. The continuous curve is the fitted parabola for the present patients
(men and women), and the dashed (women) and dotted (men) curves are the parabolas
for ISO 7029 norms given the same offset as the patients. The asterisk in
A and B represents outlying values (one case excluded from the analyses).
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The threshold data (Figure 4)
behave similar to presbyacusis in the midfrequency range (1-2 kHz). At 0.25
kHz, the ISO 7029 acceleration coefficient a (0.0030
dB · y-2 for men and women) is below the lower limit
of the 95% confidence interval of the fitted value (0.0093 dB · y-2; 95% confidence limits, 0.0056-0.0130 dB · y-2). The same applies to the values at 0.5 kHz (ISO 7029 value, 0.0035
dB · y-2; fitted value, 0.0075 dB · y-2; 95% confidence limits, 0.0046-0.0100 dB · y-2). At an age relating to generation III, the difference is maximal (Figure 4A-B). The thresholds at 4 and 8 kHz
show accelerations that are fairly close to those in normal women (Figure 4E-F, generation III), although there
were more men (n = 14) than women (n = 6) in our series.
COMMENT
The DFNA13 locus originally was mapped to chromosome 6p using a portion
of this American family.9 Expansion of the
pedigree permitted locus refinement and eventually the demonstration of a
missense mutation in the COL11A2 gene that segregated
with the hearing loss phenotype.10 The mutation,
a C-to-T transition in exon 42, results in an arginine-to-cysteine substitution.
The hearing loss may be caused by altered type II collagen spacing in the
tectorial membrane, as suggested by histopathological and electron microscopic
findings in mice with a col11a2 gene mutation.10
The phenotypic characteristics of the family have been described only
briefly,10 and the results of this study complement
that description in detail. The sensorineural hearing impairment segregating
in this family is autosomal dominant, presumably prelingual, and nonprogressive,
and it affects the midfrequency range. Our presumption that it is prelingual
is based on its lack of progression and our finding of a mean threshold in
the younger generations that differs significantly from 0.
This pattern of hearing loss is similar to the hearing loss in the only
other DFNA13 family (a Dutch kindred) that is known to segregate for a COL11A2 gene mutation.20
Affected persons in the Dutch family carry a G-to-A transition in exon 31
of the COL11A2 gene that results in a glycine-to-glutamate
amino acid substitution. Their sensorineural hearing loss is presumably prelingual
and clearly nonprogressive. Like their affected American counterparts, affected
Dutch persons present with midfrequency loss. Age-corrected thresholds, however,
are about 10 dB better at 0.25 to 4 kHz and about 25 dB worse at 8 kHz. This
additional high-frequency hearing impairment in the Dutch family persists
after correction for presbyacusis.
Syndromic COL11A2-associated hearing loss is
somewhat different. As reported by Admiraal et al15
in their study of a Dutch family with STL2 carrying a G-to-A transition that
causes in-frame skipping of a 54–base pair exon encoding 18 amino acid
residues within the triple helical and C-propeptide domains of the 2(XI) collagen molecule,12 the mean sensorineural
threshold was 40 dB (n = 14). There was no substantial progression, and the
audiometric configuration, as classified by criteria used in this study, showed
substantial variability. Most cases were downsloping, and in addition to sensorineural
hearing impairment, almost half of affected persons showed a conductive loss,
perhaps attributable to the associated features of STL2. A fairly similar
type of hearing loss was reported in a second family with STL2 in whom an
in-frame deletion removes 3 repeats of 2 unspecified amino acids and glycine
in the midportion of the 2(XI) major triple helical domain.14
Progression in hearing impairment in the American family is similar
to the ISO 7029 standard curves for presbyacusis at 1 to 2 kHz (Figure 4C-D). At lower frequencies (0.25-0.5 kHz), there is more
progression than predicted by the ISO 7029 (P50) norm. At higher frequencies
(4-8 kHz), the parabolic curve for the combined group of male and female patients
is fairly similar to the standard presbyacusis norm for women, although there
is a predominance of men in our series. These findings suggest that presbyacusis
in the American DFNA13 family is less severe than normal at the higher frequencies.
The possibility that presbyacusis is milder in this family because of
other, as yet unidentified, genetic factors cannot be excluded. It is intriguing,
however, that fairly similar observations have been reported in 2 other families
with midfrequency hearing impairment at the DFNA8 or DFNA12 locus.21, 22 These families, one Austrian and
the other Belgian, show less progression of hearing loss with age than the
normal population. Their deafness is due to mutations in the -tectorin
gene (TECTA).23 Like the COL11A2 gene, the -tectorin gene produces an important component
of the tectorial membrane. Perhaps, by changing the mechanical properties
of the tectorial membrane, it may be possible to modify the "wear and tear"
effects of age on auditory function.
AUTHOR INFORMATION
Accepted for publication August 11, 2000.
This study was supported in part by grant RO1-DC03544 from the National
Institutes of Health, Bethesda, Md (Dr Smith); by the Heinsius Houbolt Foundation,
Wassenaar, the Netherlands (Dr Cremers); and by the Nijmegen KNO-Research
Foundation, Nijmegen, the Netherlands (Dr Cremers).
From the Department of Otorhinolaryngology, University Medical Centre
St Radboud, Nijmegen, the Netherlands (Drs De Leenheer, Kunst, Huygen, and
Cremers); and the Molecular Otolaryngology Research Laboratories, Department
of Otolaryngology–Head and Neck Surgery, The University of Iowa, Iowa
City (Drs McGuirt, Prasad, Brown, and Smith).
Corresponding author: Cor W. R. J. Cremers, PhD, Department of Otorhinolaryngology,
University Medical Centre St Radboud, PO Box 9101, 6500 HB, Nijmegen, the
Netherlands (e-mail: d.helsper{at}kno.azn.nl).
REFERENCES
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1. Van Camp G, Smith RJH. Hereditary Hearing Loss Homepage. Available at: http://dnalab-www.uia.ac.be/dnalab/hhh/.
Accessed October 31, 2000.
2. Petit C. Genes responsible for human hereditary deafness: symphony of a thousand. Nat Genet. 1996;14:385-391.
FULL TEXT
|
ISI
| PUBMED
3. Weil D, Blanchard S, Kaplan J, et al. Defective myosin VIIA gene responsible for Usher syndrome type IB. Nature. 1995;374:60-61.
FULL TEXT
| PUBMED
4. Liu XZ, Walsh J, Mburu P, et al. Mutations in the myosin VIIA gene cause non-syndromic recessive deafness. Nat Genet. 1997;16:188-190.
FULL TEXT
|
ISI
| PUBMED
5. Weil D, Küssel P, Blanchard S, et al. The autosomal recessive isolated deafness, DFNB2, and the Usher 1B
syndrome are allelic defects of the myosin-VIIA gene. Nat Genet. 1997;16:191-193.
FULL TEXT
|
ISI
| PUBMED
6. Liu XZ, Walsh J, Tamagawa Y, et al. Autosomal dominant non-syndromic deafness caused by a mutation in the
myosin VIIA gene. Nat Genet. 1997;17:268-269.
FULL TEXT
|
ISI
| PUBMED
7. Everett LA, Glaser B, Beck JC, et al. Pendred syndrome is caused by mutations in a putative sulphate transporter
gene (PDS). Nat Genet. 1997;17:411-422.
FULL TEXT
|
ISI
| PUBMED
8. Li XC, Everett LA, Lalwani AK, et al. A mutation in PDS causes non-syndromic recessive
deafness. Nat Genet. 1998;18:215-217.
FULL TEXT
|
ISI
| PUBMED
9. Brown MR, Tomek MS, Van Laer L, et al. A novel locus for autosomal dominant nonsyndromic hearing loss, DFNA13,
maps to chromosome 6p. Am J Hum Genet. 1997;61:924-927.
ISI
| PUBMED
10. McGuirt WT, Prasad SD, Griffith AJ, et al. Mutations in COL11A2 cause non-syndromic hearing
loss (DFNA13). Nat Genet. 1999;23:413-419.
FULL TEXT
|
ISI
| PUBMED
11. Brunner HG, van Beersum SEC, Warman ML, Olsen BR, Ropers H-H, Mariman ECM. A Stickler syndrome gene is linked to chromosome 6 near the COL11A2
gene. Hum Mol Genet. 1994;3:1561-1564.
FREE FULL TEXT
12. Vikkula M, Mariman ECM, Lui VCH, et al. Autosomal dominant and recessive osteochondrodysplasias associated
with the COL11A2 locus. Cell. 1995;80:431-437.
FULL TEXT
|
ISI
| PUBMED
13. Mayne R, Brewton RG, Mayne PM, Baker JR. Isolation and characterization of the chains of type V/type XI collagen
present in bovine vitreous. J Biol Chem. 1993;268:9381-9386.
FREE FULL TEXT
14. Sirko-Osadsa DA, Murray MA, Scott JA, Lavery MA, Warman ML, Robin NH. Stickler syndrome without eye involvement is caused by mutations in
COL11A2, the gene encoding the 2(XI) chain of type XI collagen. J Pediatr. 1998;132:368-371.
FULL TEXT
|
ISI
| PUBMED
15. Admiraal RJC, Brunner HG, Dijkstra TL, Huygen PLM, Cremers CWRJ. Hearing loss in the nonocular Stickler syndrome caused by a COL11A2 mutation. Laryngoscope. 2000;110:457-461.
FULL TEXT
|
ISI
| PUBMED
16. Pihlajamaa T, Prockop DJ, Faber J, et al. Heterozygous glycine substitution in the COL11A2 gene in the original
patient with the Weissenbacher-Zweymüller syndrome demonstrates its identity
with heterozygous OSMED (nonocular Stickler syndrome). Am J Med Genet. 1998;80:115-120.
FULL TEXT
|
ISI
| PUBMED
17. ISO 7029. Acoustics: Threshold of Hearing by Air Conduction
as a Function of Age and Sex for Otologically Normal Persons. Geneva, Switzerland: International Organization for Standardization;
1984.
18. European Work Group on Genetics of Hearing Impairment. Infoletter 2. November 1996.
19. Documenta Geigy: Scientific Tables. 5th ed. Basel, Switzerland: S Karger AG; 1959:47.
20. Kunst H, Huybrechts C, Marres H, Huygen P, Van Camp G, Cremers C. The phenotype of DFNA13/COL11A2: non-syndromic
autosomal dominant mid- and high-frequency sensorineural hearing impairment. Am J Otol. 2000;21:181-187.
FULL TEXT
|
ISI
| PUBMED
21. Kirschhofer K, Kenyon JB, Hoover DM, et al. Autosomal-dominant, prelingual, nonprogressive sensorineural hearing
loss: localization of the gene (DFNA8) to chromosome 11q by linkage in an
Austrian family. Cytogenet Cell Genet. 1998;82:126-130.
FULL TEXT
|
ISI
| PUBMED
22. Govaerts PJ, De Ceulaer G, Daemers K, et al. A new autosomal-dominant locus (DFNA12) is responsible for a nonsyndromic,
midfrequency, prelingual and nonprogressive sensorineural hearing loss. Am J Otol. 1998;19:718-723.
ISI
| PUBMED
23. Verhoeven K, Van Laer L, Kirschhofer K, et al. Mutations in the human -tectorin gene cause autosomal dominant
non-syndromic hearing impairment. Nat Genet. 1998;19:60-62.
FULL TEXT
|
ISI
| PUBMED
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