Prevalence of Hearing Impairment
• 28 million Americans
• 2 million profoundly deaf
• 1/1000 congenitally deaf
• 1/3 impaired by age 65
• 1/2 impaired by age 80
NIDCD National Strategic Research Plan, 1989

• Dominant, recessive, X-linked, mitochondrial, or chromosomal
• Congenital or have a post-natal onset
(prelingual or postlingual)
• Stable or progressive
• Conductive, sensorineural or mixed
• An isolated finding or part of a syndrome

• Inaccessible to direct observation
• Located in the densest bone in the body
• Pathological studies are often much delayed
• Unparalleled genetic heterogeneity
• Deaf x deaf matings due to linguistic homogamy

http://www.people.virginia.edu/~rjh9u/gif/deafmute.gif

Cx26

Syndrome Gene
Alport
Branchio-Oto-Renal
Crouzon FGF
Jervell and Lange-Nielsen KCNQ1, KCNE1/IsK
Mitochondrial (MELAS, MERRF) tRNA leu(UUR) ,tRNA lys
Neurofibromatosis type II NF2
Norrie
Pendred
Stickler
Osteogenesis Imperfecta
Tranebjaerg-Mohr (DFN1)
COL4A5, COL4A3, Col4A4
EYA1
NDP
COL1A1, COL1A2
PDS
DDP
COL2A1, COL11A2, COL11A1
TCOF1 Treacher Collins
Usher
Waardenburg
MYO7A, USH2A, USH1C, CDH23
PAX3, MITF, EDNRB, EDN3, SOX10

PAX3 at 2q35
See Ishikiriyama et al ., 1989

• C.H. Usher documented the association of deaf/blindness and its inheritance in an autosomal recessive fashion in 1914
• ~50% of the deaf/blind population has
Usher syndrome
• Type I Usher Syndrome is three times more common than type II or III

Hearing Vestibular Vision Min. # # genes loss loss genes Id’d
Type I congenital absent profound onset 1 st decade
Type II
Type III congenital normal sloping onset 1 st or 2 nd decade progressive variable variable
7
3
1
3
1
0

™
Syndromic - systemic neuromuscular syndromes, diabetes & deafness, PPK & deafness
™
Nonsyndromic - A1555G 12S rRNA
A7445G tRNAser
™
Ototoxic - A1555G (12S rRNA)

• Modifier gene: a particular allele of one gene affects the expression of a second gene and thereby modifies the phenotype
• Affect the age of onset, progression, severity, or penetrance of hearing loss
• May mediate normal or abnormal function; can prevent or worsen the hearing loss caused by the second gene

• moth1 mutations prevents/worsens tubby mouse deafness
(Ikeda et al . 1999)
• mdfw mouse locus prevents/worsens deafwaddler deafness
(Noben-Trauth et al. 1997)
• A nuclear locus causes A1555G mitochondrial deafness in absence of aminoglycosides
(Bykhovskaya et al. 2000)
• DFNM1 locus prevents DFNB26 deafness
(Riazuddin et al. 2000)

Environmental
~50%
Deafness
~50%
Genetic
30%
70%
Syndromic
Alport
Pendred
Norrie
Usher
Waardenburg
Branchio-Oto-Renal
Jervell and Lange Nielsen
~15%
Non-syndromic
Autosomal Dominant
(DFNA1-DFNA39)
~80%
~3%
Autosomal Recessive
(DFNB1-DFNB30)
X-Linked
(DFN1-DFN8)
~2% Mitochondrial
Jan2001

36
35
34
33
32
31
DFNA2 p q
22
21
13
11
12
21
22
23
24
25
31
DFNA37
DFNA7
32
41
42
43
44
1
DFNA34
32
33
34
35
36
37
13
12
11
11
12
13
14
21
22
23
24
31
25
24
23
22
21
16
15
2
DFNB9 26
25
24
23
22
21 p
14
13
12
DFNB27
DFNA16 q
12
13
21
22
23
24
25
26
27
28
29
3
16
15 p 14
13
12
12
DFNB6 q 13
21
22
24
25
26
27
DFNA18 28
DFNB15
31
32
33
34
35
4
DFNA6,14,38
DFNA24
DFNB25 p
DFNA27 q
15
14
13
11
11
12
13
14
15
21
22
23
DFNB26
31
32
33
34
35
DFNA24
5 p
25
24
23
22
21
12
DFNA1
DFNA15 q
13
14
15
16
21
22
23
24
25
26
27
6
DFNA13 p
DFNA22 q
DFNA10
22
21
15
14
13
12
11
11
21
22
31
32
33
35
36
7
DFNA5
DFNB17
DFNB4
DFNB14
DFNB13
23
22
21 p
12
11 q
12
13
21
22
23
24
8
DFNA28 p
24
23
22
21
13
12 q
12
13
21
22
31
32
33
34
9
DFNB7,11
DFNA36
15
14
13 p 12
11 q
11
21
22
23
24
25
26
10
DFNB30
DFNA19
DFNB23
DFNB12
15 p q
14
13
12
11
12
13
14
21
22
23
24
25
11
DFNA32
DFNB18
DFNA11/B2
DFNA8,12/B21
DFNB24
13 p
12
11 q
12
13
14
15
21
22
23
24
DFNB20
DFNA25
DFNA41
12 p
13
12
11
12 q 13
14
21
22
31
32
33
34
13 p
13
12
11
DFNA3/B1 q
12
13
21
22
23
24
31
32
14
DFNB5
DFNA9
DFNA23 p
13
12
11
12 q 14
15
21
22
23
24
25
26
DFNA26
DFNB16
DFNA30
15 p
13
12
11 q
11.2
13
21
22
23
24
16 p q
13
12
11
12
21
22
23
24
25
DFNB3
17
DFNA20
DFNA26
January, 2002 p
11.3
11.2 q
11
12
21
22
23
18
DFNB19
13.3 p 13.2
13.1 q
12
13.1
13.2
13.3
13.4
19
13
DFNB15 p 12
11.2
DFNA4 q 12
13.2
20 p
13
11.2 q
21
22
21 p
22.3
22.1
21
11.4
11.2
p
13
12
11.2
DFNB29
DFNB8,10 q 12
13
22
DFNA17
DFNB28 q 13
21
22
23
24
25
26
27
28
X
DFN6
DFN4
DFN3
DFN2 p
11.3
q
11.2
12
Y

Nonsyndromic
Deafness
Genes
Cloned
DFN3
DFNB1/A3
DFNA11/B2
POU3F4 (POU3F4)
GJB2 (connexin 26)
MYO7A ( myosin VIIA)
1995
1997
1997
DFNA1
DFNB4
Near DFNA2
DFNA5
DFNA9
DIAPH1 (diaphanous 1) 1997
PDS (pendrin) 1997
GJB3 (connexin 31)
DFNA5 (DFNA5)
1998
1998
COCH (COCH) 1998
DFNA15
DFNB3
POU4F3
MYO15
(POU4F3) 1998
(myosin XV)
DFNA8/A12/B21 TECTA ( α -tectorin)
Near DFNA2 KCNQ4 (KCNQ4)
1998
1998
1999
DFNB9 OTOF (otoferlin)
Near DFNA3/B1 GJB6 (connexin 30)
DFNA13
DFNB8/B10
1999
1999
COL11A2 (collagen type XI α 2) 1999
TMPRSS3 (serine protease 3) 2000
DFNA10
DFNB29
DFNA17
DFNB12
EYA4 (EYA4)
CLDN14 (claudin-14)
MYO9 (myosin IX)
CHD23 (cadherin-23)
2000
2000
2000
2001

Autosomal Recessive nonsyndromic hearing loss tends to be: prelingual, stable, affecting all frequencies
Autosomal Dominant nonsyndromic hearing loss tends to be: postlingual, progressive, affecting a subset of frequencies

Genetic Linkage
Pedigree analysis of isolated populations
Tissue Specific Approaches
Inner ear cDNA libraries
Microarray expression profiling
Model System Approaches
Mouse, fly, fish…

DFNA1 pedigree
See Lynch et al., Science 1997, 27b:1223

DFNB17 family from the Madras region of India
See American Journal of Medical Genetics 78:107–113 (1998), Grienwald et al.

Figure 1. Haplotype analysis showing selected markers in the Palestinian DFNB10 family (BT117)
See Berry, et al, Genomics 68, 22–29 (2000)

Human-Mouse Homology Map
See Molecular Biology of the Cell, Vol. 4, Alberts et al.

Gene/Mutation Identification
1) Family Discovery and
Pedigree Construction
Connexin 26 Gene
. .
. .
. A G A T G A G C A . .
. A G A T T A G C A . .
Hearing
Deaf
4) Mutation Analysis
1 2 3 4 5 6 7 8
9 10 11 12 13 14 15 16
17 18 19 20 21 22 X Y
2) Linkage Analysis
SGCG
GJB2
DFNB1
FGF9
SAP18
13
3) Positional Cloning

See Leon et. al, Proceedings of the National Academy of Science, 89 (1992) C. National Academy of Sciences.

hDIAPH SSCP analysis and expression profile
See Lynch et al., Science 1997, 27b:1223

Mutations in the DFNA1 genomic and cDNA sequences
See Lynch et al., Science 1997, 27b:1223

• Mating type hearing x hearing
% Deaf offspring
0.1% hearing x deaf deaf x deaf
7%
10%

deaf vs . Deaf

Additional Readings
Lynch et al., Science 1997, 27b:1223