Molecular Vision 2010; 16:650-664 <http://www.molvis.org/molvis/v16/a74>
Received 15 July 2009 | Accepted 6 April 2010 | Published 13 April 2010
© 2010 Molecular Vision
Nonsense mutation in TMEM126A causing autosomal recessive
optic atrophy and auditory neuropathy
Esther Meyer,1 Michel Michaelides,2,3 Louise J. Tee,1 Anthony G. Robson,2,3 Fatimah Rahman,1
Shanaz Pasha,1 Linda M. Luxon,4,5 Anthony T. Moore,2,3 Eamonn R. Maher1
1Department
of Medical and Molecular Genetics, Institute of Biomedical Research, University of Birmingham, Birmingham, UK;
Institute of Ophthalmology, 11-43 Bath Street, London, UK; 3Moorfields Eye Hospital, City Road, London, UK; 4UCL Ear
Institute, 332 Grays Inn Road, London, UK; 5Great Ormond Street Hospital for Children, Great Ormond Street, London, UK
2UCL
Purpose: To define the phenotype and elucidate the molecular basis for an autosomal recessively inherited optic atrophy
and auditory neuropathy in a consanguineous family with two affected children.
Methods: Family members underwent detailed ophthalmologic, electrophysiological, and audiological assessments. An
autozygosity mapping strategy using high-density single nucleotide polymorphism microarrays and microsatellite markers
was used to detect regions of genome homozygosity that might contain the disease gene. Candidate genes were then
screened for mutations by direct sequencing.
Results: Both affected subjects had poor vision from birth and complained of progressive visual loss over time. Current
visual acuity ranged from 6/60 to 6/120. Fundus examination revealed bilateral temporal optic nerve pallor in both patients
with otherwise normal retinal findings. International-standard full-field electroretinograms were normal in both
individuals, with no evidence of generalized retinal dysfunction. Pattern cortical visual evoked potentials were grossly
abnormal bilaterally in both cases. The pattern electroretinogram N95:P50 ratio was subnormal, and the P50 was of
shortened peak time bilaterally in both patients. The electrophysiological findings were consistent with bilateral retinal
ganglion cell/optic nerve dysfunction. Audiological investigation in both siblings revealed abnormalities falling within
the auditory neuropathy/dysynchrony spectrum. There were no auditory symptoms and good outer hair cell function (as
demonstrated by transient evoked otoacoustic emissions) but impaired inner hair cell/neural function with abnormal
stapedial reflex thresholds and abnormal or absent auditory brainstem-evoked responses. The single nucleotide
polymorphism microarray data demonstrated a 24.17 Mb region of homozygosity at 11q14.1–11q22.3, which was
confirmed by microsatellite marker analysis. The candidate target region contained the transmembrane protein 126A
(TMEM126A) gene, and direct sequencing identified a previously described nonsense mutation (c.163C>T; p.Arg55X).
Conclusions: We describe the first detailed phenotyping of patients with autosomal recessive TMEM126A-associated
optic atrophy and auditory neuropathy. These findings will facilitate the identification of individuals with this recently
described disorder.
Primary hereditary optic neuropathies comprise a group
of disorders that are characterized by visual loss due to retinal
ganglion cell death. The most common forms of optic
neuropathy are Leber hereditary optic neuropathy (LHON)
with mitochondrial transmission (OMIM 535000) and
autosomal dominant optic atrophy (OMIM 165500) [1].
Autosomal recessive optic neuropathies are uncommon and
are mostly observed in association with multisystem diseases.
A few cases of isolated autosomal recessive optic atrophy
have been reported [2]. Previously Barbet et al. [3] mapped a
locus for early onset but slowly progressive optic neuropathy
(OPA6; OMIM 258500) to chromosome 8q. Affected family
members presented with visual impairment commencing
between 2 and 6 years of age, moderate photophobia, and
dyschromatopsia. There were no associated systemic features.
Recently, Hanein et al. [4] identified a second locus for
autosomal recessive optic atrophy on chromosome 11 and
identified germline mutations in transmembrane protein 126A
gene (TMEM126A) in affected individuals from four families.
Autosomal recessive auditory neuropathy has been
reported in association with mitochondrial myopathy and
mitochondrial DNA multiple deletions [5], but commonly it
presents as congenital nonsyndromic hearing impairment as a
consequence of mutations in the otoferlin (OTOF) gene, a
membrane-anchored calcium-binding protein that plays a role
in the exocytosis of synaptic vesicles at the auditory inner hair
cell ribbon synapses [6]. Nonsyndromic autosomal recessive
auditory neuropathy has also been reported in association with
missense mutations in the autosomal recessive deafness 59
gene on chromosome 2q31.1-q31.3, which encodes the
protein pejvakin found in hair cell, supporting cells, spiral
ganglion cells, and the first three relays of the afferent auditory
pathway [7].
Correspondence to: Eamonn R. Maher, Department of Medical and
Molecular Genetics, Institute of Biomedical Research, University of
Birmingham, Birmingham, UK; Phone: +44 121 627 2741; FAX:
+44 121 627 2618; email: e.r.maher@bham.ac.uk
650
Sex
Age
Symptoms
IV:1
F
19
Reduced vision
since birth
IV:2
M
17
Reduced vision
since birth;
horizontal
nystagmus; right
exotropia
TABLE 1. SUMMARY OF OPHTHALMOLOGICAL FINDINGS.
Presenting
Current
Refraction
Fundus
visual acuity
visual acuity
OD-OS
OD-OS
3/36–3/36 (14y)
6/95–6/95
−0.75/-0.25x180
Bilateral
−0.75/-0.25x180
marked
temporal
optic nerve
pallor
6/60 – 6/60 (12y)
6/120–6/60
−0.75/-0.50x90
Bilateral
plano/-0.50x15
temporal
optic nerve
pallor
ERG
Normal
Normal
PERG
Pattern and flash
VEPs
N95:P50 ratio is
subnormal and
P50 is of short
peak time
bilaterally
N95:P50 ratio is
subnormal and
P50 is of short
peak time
bilaterally
Severely abnormal
pattern and flash
VEPs bilaterally.
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651
Patient
Severely abnormal
pattern VEPs. Flash
VEPs within normal
limits.
Abbreviations: OD-OS represents: Oculus Dexter - Oculum Sinister; ERG represents Electroretinogram; PERG represents Pattern ERG; VEP represents Visual
Evoked Potential; F represents Female; M represents Male; y represent Year.
© 2010 Molecular Vision
Molecular Vision 2010; 16:650-664 <http://www.molvis.org/molvis/v16/a74>
© 2010 Molecular Vision
Figure 1. Fundal appearance. Color fundus photographs of both eyes of the two affected siblings. Bilateral temporal optic disc pallor and
normal retinal appearance (IV:1 above and IV:2 below) are seen.
a mutation in TMEM126A. Our findings suggest that auditory
neuropathy may be an additional previously unreported
feature of this disorder.
The co-occurrence of optic neuropathy and auditory
neuropathy is rare, but two cases of LHON with auditory
neuropathy have been reported [8], although a more recent
study has documented that this is an uncommon finding in
LHON [9]. The X-linked recessive deafness-dystonia-optic
neuronopathy syndrome (Mohr-Tranebjaerg syndrome;
OMIM 304700) is characterized by postlingual sensorineural
hearing loss in early childhood, with progressive neural
degeneration affecting the brain, eighth cranial nerve, and
optic nerves in adult life. The auditory findings indicate
auditory neuropathy, with spiral ganglion cells being the
suspected site of pathology. The X-linked recessive deafnessdystonia-optic neuronopathy is caused by mutations in the
translocase of inner mitochondrial membrane 8 homolog A
(yeast) gene which is also called deafness/dystonia peptide
gene and encodes for a 97 amino acid polypeptide [10].
METHODS
Patients: A consanguineous family of Algerian origin with
two affected children was ascertained and recruited for
clinical and molecular genetic studies. All subjects gave
written informed consent. The study was approved by the
South Birmingham Local Research Ethics Committee and
was performed in accordance with the Declaration of
Helsinki. Genomic DNA from the two affected individuals,
two unaffected siblings, and the parents were extracted from
peripheral lymphocytes by standard techniques.
Ocular assessment: Both affected siblings (IV:1 and IV:2)
were examined. A medical and ophthalmic history was taken,
and a full ophthalmologic examination was performed. Color
vision was tested using Ishihara pseudoisochromatic plates
and Hardy, Rand and Rittler plates (American Optical
We report the results of detailed clinical,
electrophysiological, audiological, and molecular genetic
investigations in a family with optic atrophy associated with
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Figure 2. Retinal nerve fiber layer analysis. The results of this analysis demonstrates the marked global reduction in nerve fiber layer thickness
compared to normative values (using the Zeiss Stratus® OCT 3) in Patient IV:1.
Company, New York, NY). Each patient underwent color
fundus photography, Goldmann perimetry (Haag-Streit AG,
Bern, Switzerland), and retinal nerve fiber layer analysis using
the Zeiss Stratus® OCT 3 (Carl Zeiss Meditec Inc., Dublin,
CA). Both patients had detailed electrophysiological
assessment, including a full-field electroretinogram (ERG)
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Figure 3. International-standard full-field electroretinogram of the two affected individuals of the optic atrophy family. This figure shows the
electroretinogram (ERGs) from the right (row 1) and left (row 2) eye of patient IV:2, from the right (row 3) and left (row 4) eye of patient IV:
1, and typical normal examples for comparison (row 5, bottom row). Dark-adapted ERGs are shown for flash intensities of 0.01 and 11.5 cd
seconds per square meter (cd.s.m−2); light adapted ERGs are shown for 30 Hz flicker and 2 Hz stimulation at a flash intensity of 3.0 cd.s.m
−2. ON-OFF ERGs used an orange stimulus (560 cds per square meter [cd.m−2], duration 200 ms) superimposed on a green background (150
cd.m−2). S-cone ERGs used a blue stimulus (445 nm, 80 cd.m−2) on an orange background (620 nm, 560 cd.m−2). Broken lines replace blink
artifacts occurring just after the b-wave peak in patient IV:1.
and pattern ERG, incorporating the protocols recommended
by the International Society for Clinical Electrophysiology of
Vision [11,12]. Cortical visual evoked potentials (VEPs) were
recorded to high contrast checkerboard reversal (field size
12°×15° or 24°×30°, check size 0.9°, reversal rate 2.2 Hz) and
diffuse flash stimulation.
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Figure 4. Pattern cortical visual evoked
potentials, flash cortical visual evoked
potentials,
and
pattern
electroretinograms of the two affected
individuals with mutation in the
transmembrane protein 126A gene. In
row 1 are the results from the right and
in row 2 from the left eye of patient IV:
2, in row 3 from the right and in row 4
from the left eye of patient IV:1, and in
row 5 and the bottom row from normal
examples for comparison. Illustrated
pattern cortical visual evoked potentials
(VEPs) from patient IV:2 were recorded
to a large checkerboard field (24°×30°);
those from patient IV:1 were recorded
to a standard checkerboard field
(12°×15°).
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Figure 5. Pure tone audiometry. Pure
tone audiometry (250–8000 Hz) in the
two affected siblings. The initial
recording is shown as a dashed line, and
the second recording (about 1 year later)
as a solid line. A: This panel shows pure
tone audiometric thresholds of over a 1year period of patient IV:1. B: This
panel shows pure tone audiometric
thresholds of over an 18-month period
of patient IV:2.
Audiological assessment: Both siblings underwent a detailed
otological examination and showed normal tympanic
membranes and tuning fork tests. Standard air conduction
pure tone audiometry [13] was conducted in a sound-treated
booth, using a GSI 61 audiometer (Model 61; Grason Stadler
Inc., Eden Prairie, MN) and TDH 39 headphones
(Interacoustic A/S, Assens, DK).
Brainstem-evoked potentials were recorded using a
Medelec Sensor ST10. Standard electroencephalogram
(EEG) silver/silver chloride disc electrodes were attached to
each mastoid process-A1 and A2 and to the vertex-Cz.
Electrode impedance was less than 5 kΩ. An alternating
polarity click stimulus of 100 µs electrical duration at an
intensity of 90 dBHL was presented via TDH-39 headphones
at a repetition rate of 10 Hz. Broadband noise at 50 dBHL was
used in the contralateral ear. The analysis was confined to
latencies and interwave latencies of waves I, III, and V. The
analysis of the conduction latencies was considered abnormal
if the value exceeded 2 standard deviations (SDs) from the
normal mean or if the responses were unrepeatable or absent.
Absolute interaural wave V latencies were also analyzed and
were considered to be abnormal if the latency difference of
wave V was greater than 2 standard deviations from the
normal mean.
Single frequency tympanometry was performed with a
probe signal, an 85 dB sound pressure level (SPL) continuous
tone at 226 Hz [13], using a GSI 33 Tympanometer (Model
33; Grason Stadler Inc.). Stapedial reflex thresholds were
measured both ipsilaterally and contralaterally, using the
method described by Cohen and Prasher [14].
Transient evoked otoacoustic emissions were recorded
from each ear using an Otodynamics ILO92 analyzer
(Otodynamics Ltd., Hartfield, UK) [15]. A standard nonlinear
click stimulus of 80 µs duration was presented at a repetition
rate of 50 Hz and an intensity of 80 (±3) dB SPL. The response
was averaged over 260 acquisitions, and the total (mean)
nonlinear transient evoked otoacoustic emissions (TEOAE)
response amplitude (dB SPL) was analyzed.
Linkage analysis: A genome-wide linkage scan using
Affymetrix 250K Sty1 single nucleotide polymorphism
(SNP) mapping arrays according to the manufacturer’s
instruction (Affymetrix, Inc., Santa Clara, CA) was
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Figure 6. Pure tone audiograms of
patient IV:1 (A) and patient IV:2 (B) to
show absence of air-bone gap (i.e.,
conductive hearing loss), as judged by
masked and unmasked bone conduction
thresholds.
AC
represents
air
conduction.
undertaken in all siblings to identify shared regions of
homozygosity (>2 Mb) in the affected individuals. Briefly, the
DNAs (250 ng each) were first digested with Sty1 restriction
enzyme (New England Biolabs, Boston, MA) and then ligated
to adaptors. Each Sty1 adaptor-ligated DNA was amplified in
three 100 µl PCR reactions using AmpliTaq Platinum
(Clontech Laboratories, Inc., Palo Alto, CA). Fragmented
PCR products were then labeled, denatured and hybridized to
the array following washing and staining steps on the
Affymetrix GeneChip fluidics station 450. Fluorescence
intensities were quantified with an Affymetrix array scanner
3000–7G and the data were collected by the Affymetrix
GeneChip Operating Software (GCOS) v 1.4. Genotypes were
generated using the GTYPE software for BRLMM analysis
using default settings. To evaluate common homozygous
regions, microsatellite markers were typed in all family
members. Information on primer sequences and the physical
location of the markers was obtained from the NCBI database
and from the UCSC browser, respectively. Amplification
conditions were an initial denaturation of 94 °C for 3 min,
followed by 28 cycles of 30 s denaturation at 94 °C, 30 s
annealing at 55 °C, and 30 s extension at 72 °C with a final
extension at 72 °C for 5 min. The amplified fragments were
detected by an automated ABI 3730 DNA Analyzer and
analyzed with Genemapper v3.0 software (Applied
Biosystems Inc., Foster City, CA).
followed by 35 cycles of 30 s denaturation at 95 °C, 1 min
annealing at 60 °C, and 1 min extension at 72 °C with a final
extension at 72 °C for 5 min. PCR products were cleaned up
with MicroCLEAN (Web Scientific, Crewe, UK) and were
directly sequenced by the BigDye Terminator Cycle
Sequencing System using ABI PRISM 3730 DNA Analyzer
(Applied Biosystems Inc.). DNA sequences were analyzed
using Chromas software.
RESULTS
Clinical findings: The ophthalmologic findings of the two
affected siblings are summarized in Table 1. Both subjects had
poor vision from birth and complained of a continued gradual
reduction in vision over time. Patient IV:2 had evidence of a
right exotropia and bilateral horizontal nystagmus. Neither
patient had any evidence of residual color vision. Examination
of the anterior segment was normal in both patients. Fundus
examination revealed marked bilateral temporal optic nerve
pallor in both patients with otherwise normal retinal findings
(Figure 1). Goldmann perimetry identified bilateral visual
field constriction in both patients. Retinal nerve fiber layer
analysis revealed bilateral marked reduction in nerve fiber
layer thickness in both subjects (Patient IV:1—average
thickness 38.7 μm right eye, 40.2 μm left eye; range 41.0–
54.0 μm. Patient IV:2—average thickness 40.7 μm right eye,
47.3 μm left eye; range 44.0–49.0 μm; Figure 2).
Full-field ERGs were normal in both patients, with no
evidence of generalized retinal dysfunction (Figure 3). Pattern
reversal VEPs from both patients were grossly abnormal
(Figure 4). In patient IV:2, pattern VEPs recorded to a large
checkerboard field were delayed with an abnormal waveform
bilaterally (Figure 4). Pattern VEPs to a standard
checkerboard were undetectable on the right, with only a
Mutational analysis: The family members were screened for
mutations in TMEM126A by direct sequencing. The genomic
DNA sequence of this gene was taken from Ensembl, and
primer pairs for the translated exons were designed using
primer3 software . The exons were amplified by PCR using
BioMix™ Red (Bioline Ltd., London, UK). Amplification
conditions were an initial denaturation of 95 °C for 5 min,
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Figure 7. Measurement stapedial reflex thresholds. This image is the tympanogram and ipsilateral (A) and contralateral (B) stapedial reflex
threshold recordings of patient IV:1 illustrating elevated and/or absent reflexes.
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Figure 8. Measurement stapedial reflex thresholds. This image is the tympanogram and ipsilateral (A) and contralateral (B) stapedial reflex
threshold recordings of patient IV:2 illustrating elevated and/or absent reflexes.
delayed residual component on the left (data not shown). In
patient IV:1, pattern VEPs were recorded to a standard
checkerboard and were grossly abnormal. Flash VEPs in
patient IV:1 had an abnormal waveform of low amplitude
bilaterally and revealed no definite abnormality in patient IV:
2 (Figure 4). The pattern ERG N95:P50 ratio was subnormal,
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Figure 9. Transient evoked otoacoustic emissions. Transient otoacoustic emission recordings from each ear in patient IV:1 (A) and patient
IV:2 (B) to illustrate normal cochlear outer hair cell function.
TABLE 2. BRAINSTEM EVOKED WAVE LATENCIES AND INTERWAVE INTERVALS FOR SIBLINGS AND NORMAL DEPARTMENTAL RANGES (MEAN±2SD).
Patient
Sister IL
Normal range
Brother IL
Wave 1
R
L
1.8
1.54
Wave III
R
L
3.82
3.62
Wave V
R
L
~5.24
~5.12
I-III
R
L
2.02
2.08
1.3–1.9
3.3–4.1
5.2–6.0
1.6–2.4
Absent
-
III-V
R
L
~1.96
1.6
I-V
R
L
~3.98
3.68
1.4–2.2
-
-
-
3.6–4.4
-
-
Abbreviations: R represents right; L represents left, IL represents ipsilateral recording.
and the P50 was of short peak time bilaterally in both patients
(Figure 4). These VEP and pattern ERG abnormalities are
consistent with bilateral retinal ganglion cell/optic nerve
dysfunction.
ages of 15 and 16 years (Figure 5B). Neither sibling
demonstrated a conductive loss, as judged by a masked bone
conduction threshold at 500 Hz in patient IV:1 and an
unmasked bone conduction threshold at 2,000 Hz in patient
IV:2 (Figure 6A,B). In both siblings, impedance studies
revealed normal tympanic membrane compliance and middle
ear pressures, but stapedial reflex thresholds, recording both
ipsilaterally and contralaterally from each ear, were absent in
patient IV:1 (Figure 7A,B) and elevated or absent in patient
IV:2 (Figure 8A,B). Transient evoked otoacoustic emissions
were normal in both children (Figure 9A,B), but brainstemevoked responses were abnormal. In patient IV:1, the
Audiologically, neither child complained of any auditory
or vestibular symptoms. Patient IV:1 showed a very mild low
frequency loss of auditory sensitivity in both ears on pure tone
audiometry when first tested at the age of 17 years, and this
minor loss progressed to involve the 500–4,000 Hz
frequencies in the right ear and the 8,000 Hz frequency in the
left ear, 1 year later (Figure 5A). Patient IV:2 showed a 25 dB
loss at 8 kHz in the left ear on three audiograms between the
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Figure 10. Auditory brainstem-evoked responses. A: Auditory brainstem-evoked responses for patient IV:1 (right ear upper section and left
ear lower section). B: Auditory brainstem-evoked responses for patient IV:2 (right ear upper section and left ear lower section). In patient IV:
1 the responses were of poor morphology ipsilaterally. Recording contralaterally, stimulating the left ear the response morphology was
markedly abnormal and stimulating the right ear the response was absent. In patient IV:2 all responses were absent. Abbreviations: ipsi
represents ipsilateral recording; contra represents contralateral.
responses were of poor morphology ipsilaterally (Figure
10A), although waves I and III were present and of normal
latencies (Table 2) but wave V could not be well defined.
Recording contralaterally, stimulating the left ear the response
morphology was markedly abnormal and stimulating the right
ear the response was absent. In patient IV:2, all responses were
absent (Figure 10B).
family members using microsatellite marker analysis.
Linkage to the regions on chromosome 10 and 19 was
excluded by the finding of heterozygous alleles in affected
individuals (data not shown). However, genotyping of
microsatellite markers within the candidate region at
11q14.1–11q22.3 confirmed that affected individuals were
homozygous and unaffected siblings were heterozygous
(Figure 11).
Mutation analysis of the candidate gene: The 24.17 Mb
chromosomal region at 11q14.1–11q22.3 contained 175
known genes, pseudogenes, and hypothetical proteins.
Interestingly, the TMEM126A gene that was recently
described in association with autosomal recessive optic
atrophy was located within this candidate interval. Therefore,
direct sequencing of TMEM126A was undertaken, and a
nonsense mutation was detected in exon 3 of this gene (c.
163C>T; p.Arg55X; Figure 12). The mutation co-segregated
with the disease phenotype and was found to be homozygous
in all affected individuals and heterozygous in both parents.
Previously, this mutation was not detected in 700 control
chromosomes [4].
Genetic linkage studies: Genome-wide genotyping using the
Affymetrix 250 k SNP microarrays revealed four extended
regions of homozygosity (>2 Mb; on chromosomes 10 [2 Mb;
from rs3127234 to rs912889], 11 [24.17 Mb; from
rs10793396 to rs10895556], 16 [15.16 Mb; from rs17839519
to rs7203695], and 19 [2.18 Mb; from rs670091 to
rs1654348]) shared at least by the two affected siblings. For
chromosome 16, all four children showed an almost complete
identical homozygous region of 116 SNPs from 31.63 Mb to
46.79 Mb, including the centromere. Since similar haplotypes
could be detected frequently in individuals with other
phenotypes and with different ethnic backgrounds, it was
assumed that this was unlikely to be a specific finding, and
the chromosome 16 candidate region was not further
analyzed. Additional genotyping was then performed in all
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DISCUSSION
Our findings suggest that auditory neuropathy may be a
key feature of TMEM126A-associated optic atrophy. Both
siblings demonstrated a very mild but progressive
sensorineural hearing loss, with no evidence of a conductive
loss, and normal cochlear function, as judged by normal
otoacoustic emissions; but both demonstrated abnormal
retrocochlear function, with inner hair cell/neural
involvement, as judged by abnormal stapedial reflex
thresholds and brainstem-evoked responses. The site of the
neural lesion may lie in the functional unit comprised of inner
hair cells, the primary afferents (spiral ganglion neurons), and/
or the first order synapses between hair cells and the cochlear
nerve.
We identified a homozygous nonsense mutation (c.163C>T;
p.Arg55X) in TMEM126A in an Algerian family with
recessive optic atrophy. The same mutation was identified
previously in four North African families (one Algerian, one
Tunisian, and two Moroccan) with a similar ocular phenotype
(haplotyping was consistent with a founder mutation
originating ~2,400 years ago [~80 generations]) [4]. However,
no further mutations were identified in a cohort of 48 patients
with nonsyndromic optic atrophy (in whom mutations in optic
atrophy 1 gene [OPA1] and the most frequent LHON
mutations [mitochondrial DNA {mtDNA} G11778A,
G3460A, T14484C, and G15257] had been excluded) [4]. To
date, all patients with TMEM126A mutations, including the
cases reported herein, are of Maghrebian origin and all carry
an identical mutation.
TMEM126A encodes a mitochondrial protein found in
higher eukaryotes [4]. Laboratory analysis of respiratory
chain function in patients with homozygous TMEM126A
mutations has not shown consistent abnormalities (although
one patient demonstrated partial deficiency of Complex I).
Retinal ganglion cells are located in the inner retina and their
The families described by Hanein et al. [4] were
characterized by early-onset severe visual impairment, optic
disc pallor, and central scotomata. The oldest affected patient
lost peripheral visual field function between the ages of 30
and 37. One patient also had moderate hypertrophic
cardiomyopathy, and another displayed mild hearing loss and
minor brain alterations on magnetic resonance imaging
(homogeneous punctate hyperintensities in the stratum
subependymale).
Figure 11. Pedigree diagram and haplotype analysis of the Algerian
family with autosomal recessive optic atrophy and auditory
neuropathy. The genotyping of microsatellite markers on
chromosome 11q14.1–11q22.3 (localization of markers according to
NCBI build 36.3) shows a common haplotype indicated by the black
framed boxes in the two affected members (IV:1 and IV:2). Open
squares represent unaffected males, open circles represent unaffected
females, solid squares represent affected males, solid circles
represent affected females, and the double line represent
intermarriage.
Figure 12. Sequence chromatogram of the transmembrane protein
126A gene mutation in the optic atrophy family, and their
corresponding normal sequence. A: This panel shows the
chromatogram of a control sample with wild-type allele. B: This
panel shows the chromatogram of the mother (III:1) with the
heterozygous transmembrane protein 126A gene (TMEM126A)
mutation (c.163C>T). C: This panel shows the chromatogram of an
affected individual (IV:1) with the homozygous TMEM126A variant
(c.163T). The black framed box indicates the mutation position.
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axons remain unmyelinated until they exit the globe and are
organized in bundles to form the optic nerve. During their
intraocular path, the unmyelinated axons are very energy
dependent (to transmit the action potential) and therefore
vulnerable in disorders of mitochondrial function [16]. Hence,
optic atrophy is a common feature of mitochondrial disorders,
and two other nonsyndromic causes of optic atrophy, LHON
and autosomal dominant optic atrophy Kjer type, are caused,
respectively, by mutations in mitochondrial DNA and the
nuclear gene OPA1 that encodes a mitochondrial protein. In
addition, optic atrophy is a prominent feature of many other
neurodegenerative diseases caused by primary mitochondrial
dysfunction [16]. Hearing loss is a common feature in
mitochondrial disease, although frequently cochlear
dysfunction is reported and auditory neuropathy is considered
a rare finding [5].
Interestingly, mutations in OPA1, although originally
described in nonsyndromic hereditary optic neuropathy, have
recently been reported to also cause a syndromic form of optic
atrophy associated with sensorineural deafness, ataxia, and
multiple mitochondrial DNA deletions [17,18]. The hearing
loss is reported to be suggestive of an auditory neuropathy,
while in Wolfram Syndrome or diabetes insipidus and
mellitus with optic atrophy and deafness (DIDMOAD), a
recent clinicopathological study reported cochlear
histopathological abnormalities with loss of the organ of Corti
in the basal turn of the cochlea and mild focal atrophy of the
stria vascularis [19].
Our findings suggest that a diagnosis of autosomal
recessive TMEM126A-associated optic atrophy and auditory
neuropathy (ARTOAN) should be considered in patients with
optic atrophy and deafness. Furthermore, patients with
homozygous TMEM126A mutations should be investigated
for subclinical evidence of auditory neuropathy.
3.
4.
5.
6.
7.
8.
9.
10.
11.
ACKNOWLEDGMENTS
Supported by grants from the Wellcome Trust, WellChild,
Fight for Sight (UK), the National Institute for Health
Research UK to the Biomedical Research Centre for
Ophthalmology based at Moorfields Eye Hospital NHS
Foundation Trust and UCL Institute of Ophthalmology,
Moorfields Special Trustees, the European Commission
(EVI-Genoret), Fight for Sight (USA) and the Foundation
Fighting Blindness.
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The print version of this article was created on 13 April 2010. This reflects all typographical corrections and errata to the article
through that date. Details of any changes may be found in the online version of the article.
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