Download Dia 1 - What If

GENETICS OF DEAFNESS
CONGENITAL DEAFNESS
~ 1 in 900 children has congenital hearing impairment >20 dB in one or more
frequencies
50% environmental
50 % inherited
70% Nonsyndromic
~%22
AD
~%77
AR
29
66
18
Known Genes
~%1
X-linked
30% Syndromic
<%1
Mitochondrial
•Ototoxic drugs
•Acustic trauma
•Infections
•Usher
•Alport
•Pendred
•Norrie
•Waardenburg
•Branchio-Oto-Renal
•Jervell and Lange-Nielsen
WHY IS IT IMPORTANT TO ELUCIDATE GENETIC DEFECTS
UNDERLYING HEREDITARY DISORDERS?
 Diagnosis
 To answer the question on heredity of their disease or the
disease in the family
 Adequate mutation based genetic counseling
 Early diagnoses for family members
 Insight in genes/proteins essential for development and function
of the inner ear
 Handles for therapy
DAILY PRACTICE
I:2
I:1
III:2
III:1
IV:1
IV:2
III:3
III:4
III:5
III:6
IV:3
II:4
II:3
II:2
II:1
III:7
III:8
III:9
III:10
III:11
III:12
Threshold (dB)
AUDIOGRAMS
-10
0
Cros W02011
-10
0
20
20
40
40
20
30
40
50
60
60
80
60
80
100
100
120
.25
120
.25
.5
1
2
4
Frequency
8 kHz
Cros Tamagawa
70
.5
1
2
4
8
Threshold (dB)
ARTA
-10
0
Cros W02011
-10
0
20
20
40
40
20
30
40
50
60
60
80
Cros Tamagawa
-10
0
20
0
10
20
30
40
50
60
60
80
70
40
20
60
30
40
50
80
60
100
100
100
120
.25
120
.25
120
.25
.5
1
2
4
Frequency
8 kHz
Cros Street
.5
1
2
4
8 kHz
.5
1
2
4
8 kHz
Myosin VIIa
Asn458Ile
THE INNER EAR
LESSONS FROM DEAFNESS GENES
Kazmierczak et al 2007
IDENTIFICATION OF DISEASE GENES
• Familystudies – good clinical characterization
• Identification of the chromosomal location of the genetic defect
- Linkage analysis – homozygosity mapping
• Identification of the mutated gene
- Which genes are in the linkage interval – genome browsers?
- Which of those genes are good candidates? - databases
* Expression pattern
* Function of the gene
* Animal models
* Selection of genes for mutation analysis
- Mutation analysis
- Interpretation of sequence variants
• Alternative: Next Generation sequencing
TURKISH FAMILIES - CONSANGUINITY
- Homozygous mutations
- Homozygosity mapping – linkage analysis
mutation
NM
NM
NM
x
NM
NM
x
MM
HOMOZYGOSITY MAPPING
Single Nucleotide Polymorphisms - SNPs
Person A:
Person B:
…cctcctagggttgcaaagcctccttggctatg…
…cctcctagggttgcatagcctccttggctatg…
…cctcctagggttgcatagcctccttggctatg…
…cctcctagggttgcatagcctccttggctatg…
~ 500,000 SNPs
G
T
A
C
C
C
T
G
A
T
A
A
A
T
T
G
C
T
T
G
G
C
A
G
A
T
A
A
A
T
T
A
FAMILY TR57
 Linkage interval: 11q13.2–q13.4,
 ~ 59 known genes , 18 hypothetical gene
DFNB63 LOCUS
15.5
15.4
DFNA32
12
D11S987
D11S1337
D11S4113
MYO7A
DFNB63
DFNB63
D11S4136
D11S4139
FGF3
D11S1314
D11S916
D11S2371
D11S1291
DFNB24
23.3
24.1
24.2
24.3
25
26 known or
predicted genes
DFNB51
11.2
11.12
11.11
11
12.1
12.2
12.3
13.1
13.2
13.3
13.4
13.5
14.1
14.2
14.3
21
22.1
22.2
22.3
23.1
23.2
Fam Fam
FT2 PKDF702
USH1C
14.3
14.2
14.1
13
Fam
FT1A-G
TECTA
DFNB20
D11S4179
~5.29 Mb
15.3
15.2
15.1
Fam
TR57
1.03 Mb
LRTOMT CHARACTERISATION
Genome browser build 36.1
LRTOMT1
LRTOMT2
EFFECT OF MUTATIONS
3’ UTR
A215A
R81Q
W105R
3’ UTR
G163VfsX4 (c.358+4G>A)
A29SfsX54 (c.358+4G>A)
E110K
Catechol-O-methyltransferase domein
MOLECULAR MODELING
EFFECT OF MISSENSE MUTATIONS
LRTOMT IN THE MOUSE
INNER EAR
SUMMARY
 Applied bioinformatics is essential for several
steps in disease gene identification and analyses
 The structure and function of the human genome
and genes is not completely characterized yet
 LRTOMT is the causative gene for DFNB63. The
precise effect of the mutations on inner ear
function needs to be elucidated.