Учебники / Genetic Hearing Loss Willems 2004
.pdf194 |
Fischel-Ghodsian |
mtDNA mutation in the tRNAthr gene in a family with hearing impairment and cutaneous hypopigmentation with an albinoid appearance. The Molecular Biology of Hearing and Deafness. Bethesda, MD, Oct. 4–7, 2001.
35.Jaber L, Shohat M, Bu X, Fischel-Ghodsian N, Yang HY, Wang SJ, Rotter JI. Sensorineural deafness inherited as a tissue specific mitochondrial disorder. J Med Genet 1992; 29:86–90.
36.Prezant TR, Agapian JV, Bohlman MC, Bu X, Oztas S, Qiu WQ, Arnos KS, Cortopassi GA, Jaber L, Rotter JI, Shohat M, Fischel-Ghodsian N. Mitochondrial ribosomal RNA mutation associated with both antibiotic-induced and non-syndromic deafness. Nat Genet 1993; 4:289–294.
37.Braverman I, Jaber L, Levi H, Adelman C, Arnos KS, Fischel-Ghodsian N, Shohat M, Elidan J. Audio-vestibular findings in patients with deafness caused by a mitochondrial susceptibility mutation and precipitated by an inherited nuclear mutation or aminoglycosides. Arch Otolaryngol Head Neck Surg 1996; 122:1001–1004.
¨
37a. Fischel-Ghodsian N, Prezant TR, Bu X, Oztas S. Mitochondrial ribosomal RNA gene mutation associated with aminoglycoside ototoxicity. Am J Otolaryngol 1993; 14:399–403.
38.Hutchin T, Haworth I, Higashi K, Fischel-Ghodsian N, Stoneking M, Saha N, Arnos C, Cortopassi G. A molecular basis for human hypersensitivity to aminoglycoside antibiotics. Nucleic Acids Res 1993; 21:4174–4179.
39.Matthijs G, Claes S, Longo-Mbenza B, Cassiman J-J. Non-syndromic deafness associated with a mutation and a polymorphism in the mitochondrial 12S ribosomal RNA gene in a large Zairean pedigree. Eur J Hum Genet 1996; 4: 46–51.
40.Fischel-Ghodsian N, Prezant TR, Chaltraw W, Wendt KA, Nelson RA, Arnos KS, Falk RE. Mitochondrial gene mutations: a common predisposing factor in aminoglycoside ototoxicity. Am J Otolaryngol 1997; 18:173–178.
41.Pandya A, Xia X, Radnaabazar J, Batsuuri J, Dangaansuren B, Odgerel D, Fischel-Ghodsian N, Nance WE. Mutation in the mitochondrial 12S rRNA gene in two families from Mongolia with matrilineal aminoglycoside ototoxicity. J Med Genet 1997; 34:169–172.
42.Gardner JC, Goliath R, Viljoen D, Sellars S, Cortopassi G, Hutchin T, Greenberg J, Beighton P. Familial streptomycin ototoxicity in a South African family: a mitochondrial disorder. J Med Genet 1997; 34:904–906.
43.El-Schahawi M, deMunain L, Sarrazin AM, Shanske AL, Basirico M, Shanske S, DiMauro S. Two large Spanish pedigrees with non-syndromic sensorineural deafness and the mtDNA mutation at nt 1555 in the 12SrRNA gene: evidence of heteroplasmy. Neurology 1997; 48:453–456.
44.Estivill X, Govea N, Barcelo A, Perello E, Badenas C, Romero E, Moral L, Scozzari R, D’Urbano L, Zeviani M, Torroni A. Familial progressive sensorineural deafness is mainly due to the mtDNA A1555G mutation and is enhanced by treatment with aminoglycosides. Am J Hum Genet 1998; 62: 27–35.
45.Torroni A, Cruciani F, Sellitto D, Lopez-Bigas N, Rabionet R, Govea N, Loped De Munain A, Sarduy M, Romero L, et al. The A1555G mutation in the 12S rRNA gene of human mtDNA: recurrent origins and founder events in
Mitochondrial Hearing Loss |
195 |
families a ected by sensorineural deafness. Am J Hum Genet 1999; 65:1349– 1358.
46.Pandya A, Erdenetungalag R, Xia X, Welch KO, Radnaabazar J, Dangaasuren B, Arnos KS, Nance WE. The role and frequency of mitochondrial mutations in two distinct populations: the USA and Mongolia. The Molecular Biology of Hearing and Deafness. Bethesda, MD, Oct. 4–7, 2001.
47.Usami S, Kasai AS, Shinkawa H, Moeller B, Kenyon JB, Kimberling WJ. Genetic and clinical features of sensorineural hearing loss associated with the 1555 mitochondrial mutation. Laryngoscope 1997; 107:483–490.
48.Casano RAMS, Bykhovskaya Y, Johnson DF, Torricelli F, Bigozzi M, Fischel-Ghodsian N. Hearing loss due to the mitochondrial A1555G mutation in Italian families. Am J Med Genet 1998; 79:388–391.
49.Feldmann D, Marlin S, Chapiro E, Denoyelle F, Sternberg D, Weil D, Petit C, Garabedian EN, Couderc R. Prevalence of mitochondrial mutations in familial sensorineural hearing impairment: importance of A1555G and T7511C. Am J Hum Genet 2001; 69(suppl):A2122.
50.Mingroni-Netto RC, Abreu-Silva RS, Braga MCC, Lezirovitz K, DellaRosa VA, Pirana S, Spinelli M, Otto PA. Mitochondrial mutation A1555G (12SrRNA) and connexin 26 35delG mutation are frequent causes of deafness in Brazil. Am J Hum Genet 2001; 69(suppl):A2124.
51.Reid FM, Vernham GA, Jacobs HT. Complete mtDNA sequence of a patient in a maternal pedigree with sensorineural deafness. Hum Mol Genet 1994b; 3:1435–1436.
52.Verhoeven K, Ensink RJH, Tiranti V, Huygen P, Johnson DF, Schatteman I, Van Laer L, Verstreken M, Van de Heyning P, Fischel-Ghodsian N, Zeviani M, Cremers CWRJ, Willems PJ, Van Camp G. Di erent penetrance of neurological symptoms associated with a mutation in the mitochondrial tRNASer (UCN) gene. Eur J Hum Genet 1999; 7:45–51.
53.Friedman RA, Bykhovskaya Y, Bradley R, Fallis-Cunningham R, Paradies N, Smith RJ, Grodin J, Pensak ML, Fischel-Ghodsian N. Maternal inherited deafness due to a novel genetic defect. Am J Med Genet 1999; 84:369– 372.
54.Sue CM, Tanji K, Hadjigeorgiou G, Andreu AL, Nishino I, Krishna S, Bruno C, Hirano M, Shanske S, Bonilla E, Fischel-Ghodsian N, DiMauro S, Friedman R. Maternally inherited hearing loss in a large kindred with a novel T7511C mutation in the mitochondrial DNA tRNASer(UCN) gene. Neurology 1999; 52:1905–1908.
55.Ishikawa K, Tamagawa Y, Takahashi K, Kimura H, Saito K, Ichimura K. Hereditary hearing loss in a Japanese family with a T7511C mutation in the mitochondrial tRNAser(UCN) gene. The Molecular Biology of Hearing and Deafness. Bethesda, MD, Oct. 4–7, 2001.
56.Hutchin TP, Parker MJ, Young ID, Davis A, Mueller RF. Mitochondrial DNA mutations in the tRNASer(UCN) gene causing maternally inherited hearing impairment. J Med Genet 2000; 37:692–694.
57.Konigsmark BW, Gorlin RJ. Genetic and Metabolic Deafness. Philadelphia: W.B. Saunders Co, 1976:364–365.
196 |
Fischel-Ghodsian |
58.Higashi K. Unique inheritance of streptomycin-induced deafness. Clin Genet 1989; 35:433–436.
59.Hu D-N, Qui W-Q, Wu B-T, Fang L-Z, Gu Y-P, Zhang Q-H, Yan J-H, Dingm Y-Q, Wong H. Genetic aspects of antibiotic induced deafness: mitochondrial inheritance. J Med Genet 1991; 28:79–83.
60.Stebbins WC, McGinn CS, Feitosa AG. Animal models in the study of ototoxic hearing loss. In: Lerner SA, Matz GL, Hawkins JE, eds: Aminoglycoside Ototoxicity. Boston: Little, Brown & Co., 1981:5–25.
61.Shohat M, Fischel-Ghodsian N, Legum C, Halpern GJ. Aminoglycoside induced deafness in an Israeli Jewish family with a mitochondrial ribosomal RNA gene mutation. Am J Otolaryngol 1999; 20:64–67.
62.Tono T, Kiyomizu K, Matsuda K, Komune S, Usami S, Abe S, Shinkawa H. Di erent clinical characteristics of aminoglycoside-induced profound deafness with and without the 1555 A!G mitochondrial mutation. J Oto-Rhino- Laryngol Related Spec 2001; 63:25–30.
63.Bacino CM, Prezant TR, Bu X, Fournier P, Fischel-Ghodsian N. Susceptibility mutations in the mitochondrial small ribosomal RNA gene in aminoglycoside induced deafness. Pharmacogenetics 1995; 5:165–172.
64.Casano RAMS, Johnson DF, Hamon M, Bykhovskaya Y, Torricelli F, Bigozzi M, Fischel-Ghodsian N. Inherited susceptibility to aminoglycoside ototoxicity: genetic heterogeneity and clinical implications. Am J Otolaryngol 1999; 20:151–156.
65.Nagley P, Zhang C, Martinus RD, Vaillant F, Linnane AW. Mitochondrial DNA mutations and human aging: molecular biology, bioenergetics, and redox therapy. In: DiMauro S, Wallace DC, eds. Mitochondrial DNA in Human Pathology. New York: Raven Press, 1993.
66.Fischel-Ghodsian N, Bykhovskaya Y, Taylor K, Kahen T, Cantor R, Ehrenman K, Smith R, Keithley E. Temporal bone analysis of patients with presbycusis reveals high frequency of mitochondrial mutations. Hearing Res 1997; 110:147–154.
67.Bai U, Seidman MD, Hinojosa R, Quirk WS. Mitochondrial DNA deletions associated with aging and possibly presbycusis: a human archival temporal bone study. Am J Otol 1997; 18:449–453.
68.Li M, Tzagalo A, Underbrink-Lyon K, Martin NC. Identification of the paramomycin-resistance mutation in the 15S rRNA gene of yeast mitochondria. J Biol Chem 1982; 257:5921–5928.
69.Spangler EA, Blackburn EH. The nucleotide sequence of the 17S ribosomal RNA gene of Tetrahymena thermophila and the identification of point mutations resulting in resistance to the antibiotics paromomycin and hygromycin. J Biol Chem 1985; 260:6334–6340.
70.Gravel M, Melancon P, Brakier-Gingras L. Cross-linking of streptomycin to the 16S ribosomal RNA of Escherichia coli. Biochemistry 1987; 26:6227–6232.
71.Henley CM, Schacht J. Pharmacokinetics of aminoglycoside antibiotics in blood, inner-ear fluids and tissues and their relationship to ototoxicity. Audiology 1988; 27:137–146.
Mitochondrial Hearing Loss |
197 |
72.Hamasaki K, Rando RR. Specific binding of aminoglycosides to a human rRNA construct based on a DNA polymorphism which causes aminoglyco- side-induced deafness. Biochemistry 1997; 36:12323–12328.
73.Guan M, Fischel-Ghodsian N, Attardi G. Biochemical evidence for nuclear gene involvement in phenotype of non-syndromic deafness associated with mitochondrial 12S rRNA mutation. Hum Mol Genet 1996; 5:963–972.
74.Inoue K, Takai D, Soejima A, Isobe K, Yamasoba T, Oka Y, Goto Y, Hayashi
J. Mutant mtDNA at 1555 A to G in the 12S rRNA gene and hypersusceptibility of mitochondrial translation to streptomycin can be co-transferred to U0 HeLa cells. Biochem Biophys Res Commun 1996; 223:496–501.
75.Bykhovskaya Y, Shohat M, Ehrenman K, Johnson DF, Hamon M, Cantor R, Aouizerat B, Bu X, Rotter JI, Jaber L, Fischel-Ghodsian N. Evidence for complex nuclear inheritance in a pedigree with non-syndromic deafness due to a homoplasmic mitochondrial mutation. Am J Med Genet 1998; 77: 421–426.
76.Bykhovskaya Y, Estivill X, Taylor K, Hang T, Hamon M, Casano RAMS, Yang H, Rotter JI, Shohat M, Fischel-Ghodsian N. Candidate locus for a nuclear modifier gene for maternally inherited deafness. Am J Hum Genet 2000; 66:1905–1910.
77.Bykhovskaya Y, Yang H, Taylor K, Hang T, Tun RYM, Estivill X, Casano RAMS, Majamaa K, Shohat M, Fischel-Ghodsian N. Modifier locus for mitochondrial DNA disease: linkage and linkage disequilibrium mapping of a nuclear modifier gene for maternally inherited deafness. Genet Med 2001; 3: 177–180.
78.Arnaudo E, Hirano M, Seelan RS, Milatovich A, Hsieh C, Fabriscke GM, Grossman LI, Francke U, Schon EA. Tissue-specific expression and chromosome assignment of genes specifying two isoforms of subunit VIIa of human cytochrome c oxidase. Gene 1992; 119:299–305.
79.Bindo LA, Howell N, Poulton J, McCullough DA, Morten KI, Lightowlers RN, Turnbull DM, Weber K. Abnormal RNA processing associated with a novel tRNA mutation in mitochondrial DNA. J Biol Chem 1993; 268:19559– 19564.
80.Kobayashi S, Amikura R, Okada M. Presence of mitochondrial large ribosomal RNA outside mitochondria in germ plasm of Drosophila melanogaster. Science 1993; 260:1521–1524.
81.Wang CR, Loveland BE, Fischer-Lindahl K. H-2M3 encodes the MHC class I molecule presenting the maternally transmitted antigen of the mouse. Cell 1991; 66:335–345.
82.Johnson DF, Hamon M, Fischel-Ghodsian N. Cloning and characterization of the human mitochondrial ribosomal S12 gene. Genomics 1998; 52:363–368.
83.Fischel-Ghodsian N. Mitochondrial RNA processing and translation—link between mitochondrial mutations and hearing loss? Mol Genet Metab 1998; 65:97–104.
84.Guan M, Enriquez JA, Fischel-Ghodsian N, Puranam RS, Lin C, Maw M, Attardi G. Deafness-associated mtDNA 7445 mutation has pleiotropic e ects,
198 |
Fischel-Ghodsian |
a ecting tRNASer(UCN) precursor processing and expression of NADH dehydrogenase ND6 subunit gene. Mol Cell Biol 1998; 18:5868–5879.
85.Guan M-X, Attardi G, Fischel-Ghodsian N. A biochemical basis for the inherited susceptibility to aminoglycoside ototoxicity. Hum Mol Genet 2000; 9: 1787–1793.
86.Guan M-X, Fischel-Ghodsian N, Attardi G. Transmitochondrial cell lines carrying the deafness-associated mitochondrial 12S rRNA mutation reveal a determinant role of nuclear background in the biochemical phenotype. Hum Mol Genet 2001; 10:573–580.
87.Johnson KR, Zheng QY, Bykhovskaya Y, Spirina O, Fischel-Ghodsian N. A nuclear-mitochondrial DNA interaction a ecting hearing impairment in mice. Nat Genet 2001; 27:191–194.
88.Johnson KR, Zheng QY, Erway LC. A major gene on chromosome 10 a ecting age-related hearing loss is common to at least ten inbred strains of mice. Genomics 2000; 70:171–180.
13
Gene Localization and Isolation in Nonsyndromic Hearing Loss
Patrick J. Willems
GENDIA, Antwerp, Belgium
I.GENE LOCALIZATION AND ISOLATION
Until 1992 not a single nuclear locus for nonsyndromic hearing loss (HL) had been mapped on the human genome. It is remarkable how long the genetic dissection of a very common genetic disorder such as HL lagged behind that of other sensory handicaps such as blindness. There are several explanations for this. In the first place, scientists and clinicians have always been attracted to study organs with clinically visible and/or pathologically identifiable defects such as presented by the eye. Many eye disorders can be identified by simple inspection, and classified into a large spectrum of specific defects of specific parts of the eye caused by specific genetic diseases. The cochlea, however, is still not much more than a black box with only one phenotype, hearing loss. Furthermore, owing to the inaccessibility of the auditory system, pathological studies of human HL still are scarce, and insights into the pathogenic pathways leading to HL are still based for the major part upon studies of mouse models with HL. As key proteins involved in normal hearing and HL have only been identified in the last decade, the cloning of genes implicated in human HL by functional genetics has been precluded for a long time. Also the positional cloning of HL genes lagged behind that of other disease genes.
Until 10 years ago it was generally assumed that mapping genes through linkage analysis was hardly possible in the case of HL. This assumption was based on the fact that the genetic community initially focused on prelingual HL in Western countries, as this type of HL is congenital and severe, thereby
199
200 |
Willems |
leading to deaf-mutism and social isolation in many Western countries. As prelingual HL usually has an autosomal recessive mode of inheritance, most Western pedigrees contain only a limited number of a ected family members. Furthermore, the linkage data from di erent families cannot be combined in view of the large genetic heterogeneity of nonsyndromic HL, with involvement of many genes. As the linkage power of such single one-generation pedigrees was too small to localize genes by conventional linkage analysis, hardly any recessive gene has been mapped in Western pedigrees. Another complicating factor in the localization of recessive HL loci in the Western world was the assortative mating in the deaf community, which often introduces di erent mutant genes into a single family, thereby hampering linkage analysis. However, ethnic isolates in developing countries turned out to be a reservoir of consanguineous multiplex families with autosomal recessive HL present in many family members owing to the frequent inbreeding in these countries. Another advantage of these ethnic isolates was the nearly absent assortative mating, together with the limited living area of these families with extended pedigrees living together in a small area, providing easy access to a large number of a ected family members. Most autosomal recessive forms of HL have therefore been mapped in ethnic isolates.
Another assumption precluding linkage analysis in HL was the idea that most monogenetic HL constitutes prelingual HL, which in most cases shows autosomal recessive inheritance with the above-mentioned limitations for linkage analysis. Only in the 1990s was it recognized that many individuals with monogenic HL have a postlingual progressive type of HL, with in most cases autosomal dominant inheritance. Multiplex pedigrees with many a ected family members with autosomal dominant HL turned out to be very frequent, providing enough linkage power for gene localization and isolation. This was instrumental in the localization of many forms of dominant HL. In 1992 the localization of the first autosomal dominant form of postlingual HL in an extended family from Costa Rica (1) marked the start of an impressive international e ort to hunt down the genes implicated in nonsyndromic HL.
Within the last 10 years more than 60 loci and more than 25 genes have been implicated in nonsyndromic HL (2–9). This impressive catchup in the genetic dissection of nonsyndromic HL is unparalleled in genetics. Several factors have contributed to this success. First, the human genome process has paved the way for gene localization and isolation for any given disease. In the 1980s gene localization still was painstaking owing to the paucity of highly polymorphic markers with a known position on the human genome, and the technological constraints whereby each of the markers had to be labeled radioactively and analyzed separately. Consequently, gene localization by genome screening took many months, if successful at all. Today any disease
Gene Localization and Isolation |
201 |
for which su cient linkage power is found, can be mapped on the genome in a few weeks owing to the availability of extended sets of highly informative microsatellite markers covering the whole genome, and improved technology using automated analysis of fluorescence-labeled marker sets. Other favoring factors were the development of cochlea-specific cDNA libraries that represent an excellent reservoir of candidate genes for HL (10), together with the availability of murine models for HL (11).
Finally, the setup of an international collaborative e ort with many ear, nose, and throat specialists and clinical geneticists rendered impetus to the identification of genes implicated in nonsyndromic HL.
II.LOCI FOR NONSYNDROMIC HEARING LOSS
More than 65 nuclear loci for nonsyndromic HL have been mapped on the human genome. These loci have been classified as DFN (DeaFNess) followed by a number indicating the chronological order of identification
Table 1 Autosomal Dominant Loci and Genes for Nonsyndromic HLa
Locus |
Location |
Gene |
Locus |
Location |
Gene |
|
|
|
|
|
|
DFNA1 |
5q31 |
DIAPH1 |
DFNA19 |
10 |
|
DFNA2 |
1p34 |
KCNQ4 |
DFNA20 |
17q25 |
|
|
|
GJB3 |
|
|
|
DFNA3 |
13q12 |
GJB2 |
DFNA22 |
6q13 |
MYO6 |
|
|
GJB6 |
|
|
|
DFNA4 |
19q13 |
|
DFNA23 |
14q21-22 |
|
DFNA5 |
7p15 |
ICERE1 |
DFNA24 |
4q |
|
DFNA6/14/38 |
4p16 |
WFS1 |
DFNA25 |
12q21-24 |
|
DFNA7 |
1q21–23 |
|
DFNA26 |
17q25 |
|
DFNA8/12 |
11q22–24 |
TECTA |
DFNA27 |
4q12 |
|
DFNA9 |
14q12–13 |
COCH |
DFNA28 |
8q22 |
|
DFNA10 |
6q22–23 |
EYA4 |
DFNA30 |
15q26 |
|
DFNA11 |
11q12–21 |
MYO7A |
DFNA32 |
11p15 |
|
DFNA13 |
6p21 |
COL11A2 |
DFNA34 |
1q44 |
|
DFNA15 |
5q31 |
POU4F3 |
DFNA36 |
9q13-21 |
TMC1 |
DFNA16 |
2q24 |
|
DFNA37 |
1p21 |
|
DFNA17 |
22q |
MYH9 |
DFNA41 |
12q24-ter |
|
DFNA18 |
3q22 |
|
|
|
|
aOnly loci and genes published until June 2002 are included. DFNA loci not listed here represent reserved or withdrawn loci, or loci shown to be involved in syndromic HL.
202 |
|
|
|
|
Willems |
Table 2 Autosomal Recessive Loci and Genes for Nonsyndromic HLa |
|
||||
|
|
|
|
|
|
Locus |
Location |
Gene |
Locus |
Location |
Gene |
|
|
|
|
|
|
DFNB1 |
13q12 |
GJB2 |
DFNB18 |
11p14-15 |
USH1C |
|
|
GJB6 |
|
|
|
DFNB2 |
11q13 |
MYO7A |
DFNB19 |
18p11 |
|
DFNB3 |
17p11 |
MYO15 |
DFNB20 |
11q25-ter |
|
DFNB4 |
7q31 |
SLC26A4 |
DFNB21 |
11q |
TECTA |
DFNB5 |
14q12 |
|
DFNB22 |
16p12 |
OTOA |
DFNB6 |
3p14-21 |
|
DFNB23 |
10p11-q21 |
|
DFNB7/11 |
9q13-21 |
TMC1 |
DFNB24 |
11q23 |
|
DFNB8/10 |
21q22 |
TMPRSS3 |
DFNB25 4p15-q12 |
|
|
DFNB9 |
2p22-23 |
OTOF |
DFNB26 |
4q31 |
|
DFNB12 |
10q21-22 |
CDH23 |
DFNB27 |
2q23-31 |
|
DFNB13 |
7q34-36 |
|
DFNB28 |
22q13 |
|
DFNB14 |
7q31 |
|
DFNB29 |
21q22 |
CLDN14 |
DFNB15 |
3q21-25 |
|
DFNB30 |
10p |
MYO3A |
|
or 19p13 |
|
|
|
|
DFNB16 |
15q21-22 |
STRC |
DFNB31 |
9q32-34 |
|
DFNB17 |
7q31 |
|
DFNB33 |
9q34 |
|
aOnly loci and genes published until June 2002 are included. DFNB loci not listed here represent reserved or withdrawn loci, or loci shown to be involved in syndromic HL.
of the locus. DFNA is used for autosomal dominant loci, DFNB for autosomal recessive loci, and DFN for X-linked loci. Up to June 2002, 31 DFNA loci (Table 1), 30 DFNB loci (Table 2), and four DFN loci (Table 3) had been published, with many more in press. The loci and genes are also cataloged on-line (9). All of these loci have been mapped by positional genetics using conventional linkage analysis.
Table 3 X-Linked Recessive Loci and
Genes for Nonsyndromic HLa
Locus |
Location |
Gene |
|
|
|
DFN2 |
Xq22 |
|
DFN3 |
Xq21 |
POU3F4 |
DFN4 |
Xp21 |
|
DFN6 |
Xp22 |
|
aOnly loci and genes published until June 2002 are included. DFN loci not listed here represent reserved or withdrawn loci, or loci shown to be involved in syndromic HL.
Gene Localization and Isolation |
|
203 |
|
Table 4 Genes Involved in Nonsyndromic HL |
|
||
|
|
|
|
|
|
|
Additional |
Protein |
Gene |
Nonsyndromic HL |
phenotype |
|
|
|
|
Cytoskeletal proteins |
|
|
|
Myosin VI |
MYO6 |
DFNA22 |
|
Myosin VIIA |
MYO7A |
DFNA11–DFNB2 |
Usher 1B |
Myosin XV |
MYO15 |
DFNB3 |
|
Myosin heavy |
MYH 9 |
DFNA17 |
Fechtner/May-Hegglin |
chain 9 |
|
|
|
Myosin IIIA |
MYO3A |
DFNB30 |
|
Diaphanous |
DIAPH1 |
DFNA1 |
|
Structural proteins |
|
|
|
Alpha tectorin |
TECTA |
DFNA8/12–DFNB21 |
|
Stereocilin |
STRC |
DFNAB16 |
|
Collagen type 11 |
COL11A2 |
DFNA13 |
OSMED |
Otoancorin |
OTOA |
DFNB22 |
|
Transcription factors |
|
|
|
POU3F4 |
POU3F4 |
DFN3 |
|
POU4F3 |
POU4F3 |
DFNA15 |
|
EYA4 |
EYA4 |
DFNA10 |
|
Ion transport proteins |
|
|
|
Connexin 26 |
GJB2 |
DFNA3–DFNB1 |
Vohlwinkel/PPDa |
Connexin 30 |
GJB6 |
DFNA3 |
|
Connexin 31 |
GJB3 |
DFNA2 |
Erythrokeratodermia |
Connexin 43 |
GJA1 |
|
|
Pendrin |
SLC26A4 |
DFNB4 |
Pendred |
KCNQ4 |
KCNQ4 |
DFNA2 |
|
TMC1 |
TMC1 |
DFNA36–DFNB7/B11 |
|
Claudin 14 |
CLDN14 |
DFNB29 |
|
Unknown function |
|
|
|
Icere |
DFNA5 |
DFNA5 |
|
Cochlin |
COCH |
DFNA9 |
|
Otoferlin |
OTOF |
DFNB9 |
|
CDH23 |
CDH23 |
DFNB12 |
Usher 1D |
TMPRSS3 |
TMPRSS3 |
DFNB8/B10 |
|
Wolframin |
WFS1 |
DFNA6/A14/A38 |
Wolfram |
Harmonin |
USH1C |
DFNB18 |
Usher 1C |
a PPD: palmoplantar keratodermia.