2002-7-3
R3 吳振吉
1.
1/1000: severe or profound deafness at birth or during early childhood (pre-lingual period)

60%-80% genetic
2.
1/1000: become deaf before adulthood

? % genetic
3.
30% pre-lingual deafness: syndromic
70% pre-lingual deafness: non-syndromic
4.
Non-syndromic pre-lingual hearing loss
DFNB: autosomal recessive – 85% -- 41 loci
DFNA: autosomal dominant – 15% -- 32 loci
DFN: X-linked – 1-3% -- 8 loci
5.
Causative genes:
Syndromic: ~ 100 genes
Non-syndromic: ~ 30 genes
1.
Obstacles to mapping: a.
extreme genetic heterogeneity b. absence of clinically distinctive signs for the various gene defects c.
tendency of deaf people to intermarry
2.
Segregation and linkage analysis with microsatellite polymorphic markers
3.
Candidate gene strategy:
- human cochlear cDNA library
- expressed sequence tags (ESTs): 200-400 bp partial cDNA sequences
4.
Mice models / zebrafish models
5.
In situ hybridization / immunofluorescence studies
1.
Hair cells
2.
Non-sensory cells
3.
Tectorial membrane
4.
Unknown

A. Connexin 26 Defects: DFNB1, DFNA3
1.
Epidemiology a.
DFNB1 (13q12) 30-60% autosomal recessive deafness in Europe and US
20% autosomal recessive deafness in Japan b.
Kelsell et al (1997)
GJB2 (CX26) mutation in DFNA3 and DFNB1 families c.
Estvill et al. (1998)
49% familial cases

GJB2 mutation
37% sporadic cases

GJB2 mutation
2.
Connexin: a.
Connexin

connexon (hexamer)

gap junction:
- intercellular exchange of small diffusible molecules up to 1 kDa
- functional synchronization, growth and differentiation b.
16 members named based on MW (26-60 kDa) c.
GJα & GJβ d.
Heteromeric connexon
Heterotypic channel e.
Various combination

conductance of the channel and regulation mode
(voltage, phosphorylation, pH, Ca
2+
, cyclic nucleotides) f.
Expressed in the spiral ligament, stria vascularis and the supporting cells of the organ of Corti

transcellular circulation of K
+ g.
Connexin 32: Charcot-Marie-Tooth X-linked peripheral neuropathy
Connexin 43: visceroatrial heteroataxia
Connexin 46 and 50: cataract
3.
Connexin 26 ( CX26 or GJB2 ) a.
Connexin 26: 208 a.a. = 26 kDa b.
CX26 : 2 exons (First: 5’-UTR, Second: ORF + 3’-UTR) c.
DFNA3: M34T (?), W44C,
dominant negative mutation ( Xenopus oocyte) d.
DFNB1: 50 mutations i.
European-Mediterranean: 35delG (30delG) ii.
Ashkenazi Jews: 167delT iii.Japanese: 235delC e.
Mutational hot spot / founder effects f.
Selective advantage of CX26 mutation? g.
Pitfalls for genetic counseling: 1/3 cases- difficult interpretation

4.
Clinical features of DFNB1 a.
Severity of hearing loss: highly variable b.
Audiometry: flat or sloping c.
HRCT: no anomaly d.
2/3 cases: non-progressive
B. Connexin 31 Defects: DFNA2’
GJB3
C. Connexin 30 Defects: DFNA3’
1.
Connexin 26 & connexin 30: 77% identity in a.a.

DFNA3’
2.
del Castillo (2002)
GJB2 alleles in 422 subjects

44: only one alleles

Deletion: 342 kb

Δ ( GJB6 -D13S1830)
3.
Heterozygous for point mutation in GJB2 and Δ ( GJB6 -D13S1830)
4.
Digenic inheritance
D. Pendrin Defect: DFNB4 (and Pendred Syndrome)
1.
Pendred syndrome: a.
AR b.
Prepubertal onset thyroid goiter + congenital deafness c.
Euthyroidism or hypothyroidism d.
Abnormal perchlorate test e.
Enlarged vestibular aqueduct (EVA) and Mondini deformity
2.
PDS a.
7q31 b.
21 exons c.
Pds : strongly expressed in endolymphatic duct and sac (mouse embryo)
3.
Pendrin a.
780 a.a., 86 kDa b.
11 transmembrane domains c.
Chloride and iodide transporter d.
Inner ear fluid ionic homeostasis

abnormal water and salt flux

increased endolymphatic pressure

enlarged vestibular aqueduct (EVA) and Mondini deformity e.
Lack of endolymphatic hydrops
4.
Pendred syndrome causes continuous phenotype

E. Claudin-14 Defect: DFNB29
F. Cochlin Defect: DFNA9
G EYA4 Defect: DFNA10
H. POU3F4 Defect: DFN3
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7.
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8.
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9.
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10.
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11.
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12.
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13.
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14.
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16.
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17.
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18.
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19.
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20.
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21.
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22.
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23.
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