AHL2 locus

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Otology Seminar
Age-related Hearing Loss
R3 許惇彥 2003/11/19
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Clinical Characteristics
1. Insidious onset
2. Symmetric sensorineural hearing loss
3. Progress loss with age
4. No other otologic diseases
5. Normal ear examination
Demography (1984, USA)
1. 23% of 65~75 years-old
2. 40% of older than 75 years
3. More prevalent and severe in men (esp. > 1000Hz)
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4. Late onset of auditory impairment in women
History
1. Toynbee 1849: age-related hearing loss
2. Zwaardemaker 1891: accurate description (cochlear origin)
Cochlear Pathological Findings (Schuknecht, 1964):
1. Sensory Presbycusis
Abrupt high tone loss
Loss of hair cells, atrophy of organ of Corti, typically
8~12mm from base of cochlea
 Lipofuscin pigment granules accumulation
2. Neural Presbycusis
 Mild down-sloping loss
 Poor speech discrimination (esp. involve 15-22mm from
base of cochlea) with relatively normal PTA (PTA↓ while
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loss > 90%)
Loss of > 50% cochlear neurons compared to the means
of neonates (35500) (2100 loss/decade)
3. Strial (Metabolic) Presbycusis
 Flat loss
 Loss of >30% of normal volume of strial volume
 Secondary to internal auditory artery perfusion↓
4. Cochlear conductive Presbycusis
 Linear and gradual high frequency loss, at least 50dB
between best and poorest thresholds
1
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Thickening of basal membrane, decreasing elasticity
(Basal turn > apex)
5. Mixed
6. Indetermined (25%)
Central neural presbycusis
1. Normal inner ear findings
2. Ventral cochlear nucleus, inferior colliculus, medial geniculate
body degeneration
Conductive Presbycusis
1. Tympanic membrane thickness and collagen content↓,
elasticity↓
2. Velocity transfer function↓
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Mitochondrial aging hypothesis (acquired mitochondrial defect)
ROM (Reactive Oxygen Metabolites)(free radicals)
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May naturally occur during redox reaction esp. respiratory
oxidative phosphorylation reactions
Oxidative insults occur 7 x 1012 /second /cell
Inactivate enzyme, fragment DNA, fatty acid peroxidation
Lack of histone coat protection in mitochondria
Superoxide dismutase, catalase, glutathione↓with aging
Prolonged hypoperfusion or ischemia in aging structure
↓
Bioenergetically deficient, cell structure destruction or
Apoptosis Ignition
Mitochondrial deletion in hypoxic human heart
1. Mitochondrial 4977bp deletion (between ATPase and ND5
genes) was identified more in CAD heart in human (0.85% vs.
0.0035%)
Temporal bone study
1. Significant reduction in cochlear blood flow in human inner ear
with advancing age
2. Strial vascularis cells and spiral ganglion cell body contain
greatest amount mitochondria in inner ear structure
3. Mitochondrial 4977bp deletion was identified more in human
with presbycusis (14/17 vs. 8/17, p<0.05)
2
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Genetic abnormality identified by mouse model
AHL locus
1. First identified gene causing late-onset, non-syndromic
hearing loss in more than 20 strains of mice
2. Chromosome 10, promotor region (?) of cadherin 23
3. Recessive inheritant
4. Cadherin 23: a cell-cell adhesion molecules
5. Loss of functional Cadherin --> disruption of highly organized
stereocilia bundles of hair cells in cochlea and vestibule
6. Homozygosity of AHL gene of C57BL/6J strain shew increased
sensitivity of mice to noise-induced hearing loss
7. Polymorphism in different strains showing age-related
hearing loss
AHL2 locus
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1. Possible predisposing AHL gene related hearing loss in certain
strain of mice
2. Chromosome 5
Interaction of mitochondrial DNA and nuclear DNA ?
Possible treatment
1. Mitochondrail metabolites (eq. α–lipoic acid, acetyl L
carnitine)
2. Anti-oxidants (eq. ascorbic acid, tocopherol, carotenoid)
3
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Reference
COCHLEAR PATHOLOGY IN PRESBYCUSIS Ann Otol Rhinol Laryngol
1993;102:1-16
2.
Age-related hearing loss: current research Curr Opin in Otolaryngol Head
Neck Surg 2003;11:367-71
3.
Molecular mechanisms of age-related hearing loss Ageing Reasearch Reviews
2002;1:331-43
4.
Auditory function in presbycusis: peripheral vs. central changes Experimental
Gerontology 2003;38:87-94
5.
Hypoxemia Is Associated With Mitochondrial DNA Damage and Gene Induction
Implications for Cardiac Disease JAMA 1991;266(13):1812-16
6.
Age-Related Differences in Cochlear Microcirculation and Auditory Brain Stem
Response Arch Otolaryngol Head Neck Surg 1996;122:1221-6
7.
Temporal bone analysis of patients with presbycusis reveals high frequency of
mitochondrial mutations Hear Res 1997;110:147-54
8.
Mitochondrial DNA deletions associated with aging and possibily presbycusis:
A Human Archival Temporal Bone Study Am J Otol 1997;18:449-53
9.
Mitochondrial DNA Deletions Associated With Aging and Presbycusis Arch
Otolaryngol Head Neck Surg 1997;123:1039-45
10.
Biologic Activity of Mitochondrial Metabolites on Aging and Age-related
Hearing Loss Am J Otol 2000;21:161-7
11.
Mitochondrail cytochrome oxidase immunolabeling in aged human temporal
bones Hear Res 2001;157:93-9
12.
Association of Mitochondrial DNA Deletions and Cochlear Pathology: A
Molecular Biologic Tool Laryngoscope 1996;106:777-83
13.
Effects of Dietary Restriction and Antioxidants on Presbyacusis Laryngoscope
2000;110:727-38
14.
A major gene affecting age-related hearing loss in C57BL/6J mice Hear Res
1997;114:83-92
15.
A Major Gene Affecting Age-Related Hearing Loss Is Common to at Least Ten
Inbred Strains of Mice Genomics 2000;70:171-80
16.
Genomic structure, alternative splice forms and normal and mutant alleles of
cadherin 23(Cdh23) Gene 2001;281:31-41
17.
AHl2, a Second Locus Affecting Age-Related Hearing Loss in Mice Genomics
2002;80(5):461-4
18.
Association of cadherin 23 with polygenic inheritance genetic modification of
sensorineural hearing loss NATURE GENETICS 2003;35(1):21-3
19.
Modifying with mitochondria NATURE GENETICS 2001;27:136-7
4
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