harvard-mit division of health sciences and technology hst.730 ... · syndromes, diabetes &...
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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
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Genetic hearing loss may be…
• 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
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Obstacles to Studying Genetic Deafness
• 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
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http://www.people.virginia.edu/~rjh9u/gif/deafmute.gif
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Cx26
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Syndromic Hearing Loss
Syndrome Gene Alport COL4A5, COL4A3, Col4A4 Branchio-Oto-Renal EYA1
Crouzon FGF Jervell and Lange-Nielsen KCNQ1, KCNE1/IsK Mitochondrial (MELAS, MERRF) tRNAleu(UUR),tRNAlys
Neurofibromatosis type II NF2 Norrie NDP Osteogenesis Imperfecta COL1A1, COL1A2 Pendred PDS Stickler COL2A1, COL11A2, COL11A1 Tranebjaerg-Mohr (DFN1) DDP Treacher Collins TCOF1
Usher MYO7A, USH2A, USH1C, CDH23 Waardenburg PAX3, MITF, EDNRB, EDN3, SOX10
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PAX3 at 2q35
See Ishikiriyama et al., 1989
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The Usher Syndromes
• 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
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Clinical characteristics of the
Type I
Type II
Type III
Usher syndromes
Hearing Vestibular Vision Min. # # genes loss loss genes Id’d
congenital absent onset 1st 7 3 profound decade
congenital normal onset 1st 3 1 sloping or 2nd
decade progressive variable variable 1 0
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Mitochondrial Deafness
� Syndromic - systemic neuromuscular syndromes, diabetes & deafness, PPK & deafness
� Nonsyndromic - A1555G 12S rRNA A7445G tRNAser
� Ototoxic - A1555G (12S rRNA)
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Modifier Genes of Deafness
• 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
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Deafness Modifier Genes
• 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)
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Deafness
Environmental
Genetic
~50%
30%
70%
~50%
Syndromic Alport Pendred Waardenburg Branchio-Oto-Renal Jervell and Lange Nielsen
Usher Norrie
~15%
~80%
~3%
~2%
Non-syndromic
Autosomal Recessive (DFNB1-DFNB30)
X-Linked (DFN1-DFN8)
Mitochondrial
Autosomal Dominant (DFNA1-DFNA39)
Jan2001
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25 36 24
2335 34 22 26 33
DFNA2 DFNB9 162521 DFNA6,14,38
152432 16 25 22DFNA2423 2415 1415 22 23 21 2331 p 14 DFNB25 p 1313 13 22 pppp 12
2221 1512 DFNA5 2111 1422 1112 21 DFNA13 p 1311 p 1221
DFNA2714 q 12 pDFNB6 q 13 12 1111 111213DFNA37 12 13p 21p qqqq 1213 13 12 11
14 11 q22 1314 1315 q 14 DFNA22 q 2412 211521 2112 25 2116q 2222 26DFNB27
q 1322
21 212323 27 DFNB17 2221DFNA7 DFNA2822 24 DFNA16 22 3128 DFNB4DFNA1 22 DFNA10DFNA1823 31 24
2331 32 DFNB14 23 DFNA15 2324 DFNB26 32DFNB15 3125 33 DFNB13 24
2532 33 24 3532 3431 253333 26 3635 263434 2727 35 DFNA24 832 35 28 36 29
41 6 73742 53 4
43 DFNA3444
21
15 23 24
13 22
1514 DFNA32 13 13 13
21 13DFNB30 14 pp 12 p 12 12p 12 DFNB18
p 12 p 11 11 11 13
12 13 111311 12 12DFNA19
p 11 p 12
11 12 12
q 13 DFNA26DFNA3/B1 DFNB512q 13 11qDFNB2312 13q DFNA9 q 14
15q 141413 DFNB12 q 12
21 11.2DFNB7,11 21 2115 DFNB1613 DFNA2321 DFNA11/B2 21 22 q 1322DFNA36 22 21 23 21
22 DFNA25 2214 23 2221 242223 24DFNA8,12/B21 23
31 22 312324 2531 243232 23 DFNB24 24 263333 3225 DFNA30DFNA41 342434 DFNB2026 25 16
13 14 15 9 10 11 12
22.3 DFN6 22.1
21 DFN413 p 11.4p 11.312 p13.3 13 13 1311 11.2 DFNB19 p 13.2 p p 11.3p 11.2DFNB3 12DFNB15 p 12
13.1 11.2 11.211 11.2 q 21
12 13q 12 11.2
22 12 q21
qq 13.1 DFNA17 21q 1221 DFNB29 q 12 DFN3
q DFNA4 22
24 23 13.2 DFNB2813.213.3 DFNB8,10 13
22 22 DFN2 12 25 13.4DFNA20 23 23
24DFNA26 25 Y 2717 18 19 20 21 22 26
28
January, 2002 X
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Nonsyndromic Deafness
Genes Cloned
Locus Gene (Protein) Cloned
DFN3 POU3F4 (POU3F4) 1995
DFNB1/A3 GJB2 (connexin 26) 1997
DFNA11/B2 MYO7A (myosin VIIA) 1997
DFNA1 DIAPH1 (diaphanous 1) 1997
DFNB4 PDS (pendrin) 1997
Near DFNA2 GJB3 (connexin 31) 1998
DFNA5 DFNA5 (DFNA5) 1998
DFNA9 COCH (COCH) 1998
DFNA15 POU4F3 (POU4F3) 1998
DFNB3 MYO15 (myosin XV) 1998
DFNA8/A12/B21 TECTA (α-tectorin) 1998
Near DFNA2 KCNQ4 (KCNQ4) 1999
DFNB9 OTOF (otoferlin) 1999
Near DFNA3/B1 GJB6 (connexin 30) 1999
DFNA13 COL11A2 (collagen type XI α2) 1999
DFNB8/B10 TMPRSS3 (serine protease 3) 2000
DFNA10 EYA4 (EYA4) 2000
DFNB29 CLDN14 (claudin-14) 2000
DFNA17 MYO9 (myosin IX) 2000
DFNB12 CHD23 (cadherin-23) 2001
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Autosomal Recessivenonsyndromic hearing loss tends to be:
prelingual, stable, affecting all frequencies
Autosomal Dominantnonsyndromic hearing loss tends to be:
postlingual, progressive, affecting a subset of frequencies
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Gene Discovery Methods
Genetic Linkage Pedigree analysis of isolated populations
Tissue Specific Approaches Inner ear cDNA libraries Microarray expression profiling
Model System ApproachesMouse, fly, fish…
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DFNA1 pedigree See Lynch et al., Science 1997, 27b:1223
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DFNB17 family from the Madras region of India
See American Journal of Medical Genetics 78:107–113 (1998), Grienwald et al.
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Figure 1. Haplotype analysis showing selected markers in the Palestinian DFNB10 family (BT117)
See Berry, et al, Genomics 68, 22–29 (2000)
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Human-Mouse Homology Map
See Molecular Biology of the Cell, Vol. 4, Alberts et al.
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.AGATGAGCA..
.AGATTAGCA..
Gene/Mutation Identification
1 2 3 4 5 6 7 8
9 10 11 12 13 14 15 16
17 18 19 20 21 22 X Y1) Family Discovery and Pedigree Construction 2) Linkage Analysis
Connexin 26 Gene
13 SAP18
SGCG
FGF9
GJB2
DFNB1 .. . .
Hearing Deaf
4) Mutation Analysis
3) Positional Cloning
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See Leon et. al, Proceedings of the National Academy of Science, 89 (1992) C. National Academy of Sciences.
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hDIAPH SSCP analysis and expression profile
See Lynch et al., Science 1997, 27b:1223
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Mutations in the DFNA1 genomic and cDNA sequences
See Lynch et al., Science 1997, 27b:1223
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Risk of deaf offspring
• Mating type
hearing x hearing
hearing x deaf
deaf x deaf
% Deaf offspring
0.1%
7%
10%
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deaf vs. Deaf
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Additional Readings
Lynch et al., Science 1997, 27b:1223