Учебники / Genetic Hearing Loss Willems 2004

between the basal cells of the stria vascularis by TJs (60). The onset of claudin 14 in the inner ear is temporally correlated with the appearance of the endocochlear potential (60), suggesting that claudin 14 is important for sealing the scala media. An alternative or additional role for claudin 14 in the organ of Corti might be related to its hypothesized TJ fence function in developing and maintaining the polarity of inner and outer hair cells. These two hypotheses can be tested by measuring endocochlear potential and by examining hair cell structure and integrity in Cldn14-null mice.

III.SUMMARY

Claudin 14 is required for hearing, as demonstrated by profound congenital deafness caused by homozygosity for recessive CLDN14 mutations in humans and mice. In addition to the inner ear, claudin 14 is expressed in kidney and liver, yet no obvious kidney or liver pathophysiology was observed in deaf individuals homozygous for CLDN14 mutations, or in Cldn14-null mice. This indicates that in kidney and liver claudin 14 is not necessary for normal function under regular conditions. It remains to be determined if the role of claudin 14 in the auditory system is important for paracellular transport or epithelial cell polarity and/or hair cell development. Further characterization of Cldn14-null mice will lead to a better understanding of the role of tight junctions in the development and maintenance of the processes necessary for sound transduction in the ear.

REFERENCES

1.Ferrary E, Sterkers O. Mechanisms of endolymph secretion. Kidney Int Suppl 1998; 65:S98–103.

2.Ryan AF, Wickham MG, Bone RC. Element content of intracochlear fluids, outer hair cells, and stria vascularis as determined by energy-dispersive roentgen ray analysis. Otolaryngol Head Neck Surg 1979; 87:659–665.

3.Farquhar MG, Palade GE. Junctional complexes in various epithelia. J Cell Biol 1963; 17:375–412.

4.Kowalczyk AP, Bornslaeger EA, Norvell SM, Palka HL, Green KJ. Desmosomes: intercellular adhesive junctions specialized for attachment of intermediate filaments. Int Rev Cytol 1999; 185:237–302.

5.Nagafuchi A. Molecular architecture of adherens junctions. Curr Opin Cell Biol 2001; 13:600–603.

6.Goodenough DA, Goliger JA, Paul DL. Connexins, connexons, and intercellular communication. Annu Rev Biochem 1996; 65:475–502.

7.Anderson JM. Molecular structure of tight junctions and their role in epithelial transport. News Physiol Sci 2001; 16:126–130.

8.Tsukita S, Furuse M, Itoh M. Multifunctional strands in tight junctions. Nat Rev Mol Cell Biol 2001; 2:285–293.

9.Yeaman C, Grindsta KK, Nelson WJ. New perspectives on mechanisms involved in generating epithelial cell polarity. Physiol Rev 1999; 79:73–98.

10.Staehelin LA. Structure and function of intercellular junctions. Int Rev Cytol 1974; 39:191–283.

11.Staehelin LA. Further observations on the fine structure of freeze-cleaved tight junctions. J Cell Sci 1973; 13:763–786.

12.Cereijido M, Valdes J, Shoshani L, Contreras RG. Role of tight junctions in establishing and maintaining cell polarity. Annu Rev Physiol 1998; 60:161– 177.

13.Dragsten PR, Blumenthal R, Handler JS. Membrane asymmetry in epithelia: is the tight junction a barrier to di usion in the plasma membrane? Nature 1981; 294:718–722.

14.van Meer G, Simons K. The function of tight junctions in maintaining di erences in lipid composition between the apical and the basolateral cell surface domains of MDCK cells. EMBO J 1986; 5:1455–1464.

15.van Meer G, Gumbiner B, Simons K. The tight junction does not allow lipid molecules to di use from one epithelial cell to the next. Nature 1986; 322:639– 641.

16.Madara JL. Regulation of the movement of solutes across tight junctions. Annu Rev Physiol 1998; 60:143–159.

17.Fromter E, Diamond J. Route of passive ion permeation in epithelia. Nat New Biol 1972; 235:9–13.

18.Reese TS, Karnovsky MJ. Fine structural localization of a blood-brain barrier to exogenous peroxidase. J Cell Biol 1967; 34:207–217.

19.Claude P, Goodenough DA. Fracture faces of zonulae occludentes from ‘‘tight’’ and ‘‘leaky’’ epithelia. J Cell Biol 1973; 58:390–400.

20.Furuse M, Hirase T, Itoh M, Nagafuchi A, Yonemura S, Tsukita S. Occludin: a novel integral membrane protein localizing at tight junctions. J Cell Biol 1993; 123:1777–1788.

21.Tsukita S, Furuse M. Pores in the wall: claudins constitute tight junction strands containing aqueous pores. J Cell Biol 2000; 149:13–16.

22.Martin-Padura I, Lostaglio S, Schneemann M, Williams L, Romano M, Fruscella P, Panzeri C, Stoppacciaro A, Ruco L, Villa A, Simmons D, Dejana E. Junctional adhesion molecule, a novel member of the immunoglobulin superfamily that distributes at intercellular junctions and modulates monocyte transmigration. J Cell Biol 1998; 142:117–127.

23.Williams LA, Martin-Padura I, Dejana E, Hogg N, Simmons DL. Identification and characterisation of human junctional adhesion molecule (JAM). Mol Immunol 1999; 36:1175–1188.

24.Turner JR. ‘‘Putting the squeeze’’ on the tight junction: understanding cytoskeletal regulation. Semin Cell Dev Biol 2000; 11:301–308.

25.Gonzalez-Mariscal L, Betanzos A, Avila-Flores A. MAGUK proteins: structure and role in the tight junction. Semin Cell Dev Biol 2000; 11:315–324.

26.Mitic LL, Van Itallie CM, Anderson JM. Molecular physiology and pathophysiology of tight junctions I. Tight junction structure and function: lessons from mutant animals and proteins. Am J Physiol Gastrointest Liver Physiol 2000; 279:G250–254.

27.Van Itallie CM, Anderson JM. Occludin confers adhesiveness when expressed in fibroblasts. J Cell Sci 1997; 110:1113–1121.

28.Lacaz-Vieira F, Jaeger MM, Farshori P, Kachar B. Small synthetic peptides homologous to segments of the first external loop of occludin impair tight junction resealing. J Membr Biol 1999; 168:289–297.

29.Wong V, Gumbiner BM. A synthetic peptide corresponding to the extracellular domain of occludin perturbs the tight junction permeability barrier. J Cell Biol 1997; 136:399–409.

30.Balda MS, Whitney JA, Flores C, Gonzalez S, Cereijido M, Matter K. Functional dissociation of paracellular permeability and transepithelial electrical resistance and disruption of the apical-basolateral intramembrane di usion barrier by expression of a mutant tight junction membrane protein. J Cell Biol 1996; 134:1031–1049.

31.Chen Y, Merzdorf C, Paul DL, Goodenough DA. COOH terminus of occludin is required for tight junction barrier function in early Xenopus embryos. J Cell Biol 1997; 138:891–899.

32.McCarthy KM, Skare IB, Stankewich MC, Furuse M, Tsukita S, Rogers RA, Lynch RD, Schneeberger EE. Occludin is a functional component of the tight junction. J Cell Sci 1996; 109:2287–2298.

33.Hirase T, Staddon JM, Saitou M, Ando-Akatsuka Y, Itoh M, Furuse M, Fujimoto K, Tsukita S, Rubin LL. Occludin as a possible determinant of tight junction permeability in endothelial cells. J Cell Sci 1997; 110:1603–1613.

34.Moroi S, Saitou M, Fujimoto K, Sakakibara A, Furuse M, Yoshida O, Tsukita S. Occludin is concentrated at tight junctions of mouse/rat but not human/ guinea pig Sertoli cells in testes. Am J Physiol 1998; 274:C1708–1717.

35.Saitou M, Fujimoto K, Doi Y, Itoh M, Fujimoto T, Furuse M, Takano H, Noda T, Tsukita S. Occludin-deficient embryonic stem cells can di erentiate into polarized epithelial cells bearing tight junctions. J Cell Biol 1998; 141:397–408.

36.Saitou M, Furuse M, Sasaki H, Schulzke JD, Fromm M, Takano H, Noda T, Tsukita S. Complex phenotype of mice lacking occludin, a component of tight junction strands. Mol Biol Cell 2000; 11:4131–4142.

37.Furuse M, Fujita K, Hiiragi T, Fujimoto K, Tsukita S. Claudin-1 and -2: novel integral membrane proteins localizing at tight junctions with no sequence similarity to occludin. J Cell Biol 1998; 141:1539–1550.

38.Furuse M, Sasaki H, Fujimoto K, Tsukita S. A single gene product, claudin-1 or -2, reconstitutes tight junction strands and recruits occludin in fibroblasts. J Cell Biol 1998; 143:391–401.

39.Morita K, Furuse M, Fujimoto K, Tsukita S. Claudin multigene family encoding four-transmembrane domain protein components of tight junction strands. Proc Natl Acad Sci USA 1999; 96:511–516.

40.Itoh M, Furuse M, Morita K, Kubota K, Saitou M, Tsukita S. Direct binding of three tight junction-associated MAGUKs, ZO-1, ZO-2, and ZO-3, with the COOH termini of claudins. J Cell Biol 1999; 147:1351–1363.

41.Furuse M, Sasaki H, Tsukita S. Manner of interaction of heterogeneous claudin species within and between tight junction strands. J Cell Biol 1999; 147:891– 903.

42.Sonoda N, Furuse M, Sasaki H, Yonemura S, Katahira J, Horiguchi Y, Tsukita S. Clostridium perfringens enterotoxin fragment removes specific claudins from tight junction strands: evidence for direct involvement of claudins in tight junction barrier. J Cell Biol 1999; 147:195–204.

43.Simon DB, Lu Y, Choate KA, Velazquez H, Al-Sabban E, Praga M, Casari G, Bettinelli A, Colussi G, Rodriguez-Soriano J, McCredie D, Milford D, Sanjad S, Lifton RP. Paracellin-1, a renal tight junction protein required for paracellular Mg2+ resorption. Science 1999; 285:103–106.

44.Hirano T, Kobayashi N, Itoh T, Takasuga A, Nakamaru T, Hirotsune S, Sugimoto Y. Null mutation of PCLN-1/Claudin-16 results in bovine chronic interstitial nephritis. Genome Res 2000; 10:659–663.

45.Gow A, Southwood CM, Li JS, Pariali M, Riordan GP, Brodie SE, Danias J, Bronstein JM, Kachar B, Lazzarini RA. CNS myelin and sertoli cell tight junction strands are absent in Osp/claudin-11 null mice. Cell 1999; 99:649–659.

46.Wilcox ER, Burton QL, Naz S, Riazuddin S, Smith TN, Ploplis B, Belyantseva I, Ben-Yosef T, Liburd NA, Morell RJ, Kachar B, Wu DK, Gri th AJ, Friedman TB. Mutations in the gene encoding tight junction claudin-14 cause autosomal recessive deafness DFNB29. Cell 2001; 104:165–172.

47.Gregory M, Dufresne J, Hermo L, Cyr D. Claudin-1 is not restricted to tight junctions in the rat epididymis. Endocrinology 2001; 142:854–863.

48.Kollmar R, Nakamura SK, Kappler JA, Hudspeth AJ. Expression and phylogeny of claudins in vertebrate primordia. Proc Natl Acad Sci USA 2001; 98:10196–10201.

49.Hattori M, Fujiyama A, Taylor TD, et al. The DNA sequence of human chromosome 21. Nature 2000; 405:311–319.

50.Scott HS, Kudoh J, Wattenhofer M, Shibuya K, Berry A, Chrast R, Guipponi M, Wang J, Kawasaki K, Asakawa S, Minoshima S, Younus F, Mehdi SQ, Radhakrishna U, Papasavvas MP, Gehrig C, Rossier C, Korostishevsky M, Gal A, Shimizu N, Bonne-Tamir B, Antonarakis SE. Insertion of beta-satellite repeats identifies a transmembrane protease causing both congenital and childhood onset autosomal recessive deafness. Nat Genet 2001; 27:59–63.

51.Ben-Yosef T, Wattenhofer M, Riazuddin S, Ahmed ZM, Scott HS, Kudoh J, Shibuya K, Antonarakis SE, Bonne-Tamir B, Radhakrishna U, Naz S, Ahmed Z, Pandya A, Nance WE, Wilcox ER, Friedman TB, Morell RJ. Novel mutations of TMPRSS3 in four DFNB8/B10 families segregating congenital autosomal recessive deafness. J Med Genet 2001; 38:396–400.

52.Kelsell DP, Dunlop J, Stevens HP, Lench NJ, Liang JN, Parry G, Mueller RF, Leigh IM. Connexin 26 mutations in hereditary non-syndromic sensorineural deafness. Nature 1997; 387:80–83.

53.Liu XZ, Xia XJ, Xu LR, Pandya A, Liang CY, Blanton SH, Brown SD, Steel

KP, Nance WE. Mutations in connexin 31 underlie recessive as well as dominant non-syndromic hearing loss. Hum Mol Genet 2000; 9:63–67.

54.Morell RJ, Kim HJ, Hood LJ, Goforth L, Friderici K, Fisher R, Van Camp G, Berlin CI, Oddoux C, Ostrer H, Keats B, Friedman TB. Mutations in the connexin 26 gene (GJB2) among Ashkenazi Jews with nonsyndromic recessive deafness. N Engl J Med 1998; 339:1500–1505.

55.Xia JH, Liu CY, Tang BS, Pan Q, Huang L, Dai HP, Zhang BR, Xie W, Hu DX, Zheng D, Shi XL, Wang DA, Xia K, Yu KP, Liao XD, Feng Y, Yang YF, Xiao JY, Xie DH, Huang JZ. Mutations in the gene encoding gap junction protein beta-3 associated with autosomal dominant hearing impairment. Nat Genet 1998; 20:370–373.

56.Friedman T, Battey J, Kachar B, Riazuddin S, Noben-Trauth K, Gri th A, Wilcox E. Modifier genes of hereditary hearing loss. Curr Opin Neurobiol 2000; 10:487–493.

57.Johnstone BM, Sellick PM. The peripheral auditory apparatus. Q Rev Biophys 1972; 5:1–57.

58.Gratton MA, Smyth BJ, Lam CF, Boettcher FA, Schmiedt RA. Decline in the endocochlear potential corresponds to decreased Na,K-ATPase activity in the lateral wall of quiet-aged gerbils. Hearing Res 1997; 108:9–16.

59.Marcus DC, Chiba T. K+ and Na+ absorption by outer sulcus epithelial cells. Hearing Res 1999; 134:48–56.

60.Souter M, Forge A. Intercellular junctional maturation in the stria vascularis: possible association with onset and rise of endocochlear potential. Hearing Res 1998; 119:81–95.

61.Stankovic KM, Brown D, Alper SL, Adams JC. Localization of pH regulating proteins H+ ATPase and Cl-/HCO3- exchanger in the guinea pig inner ear. Hearing Res 1997; 114:21–34.

62.Hudspeth AJ. How the ear’s works work. Nature 1989; 341:397–404.

63.Milhaud PG, Nicolas MT, Bartolami S, Cabanis MT, Sans A. Vestibular semicircular canal epithelium of the rat in culture on filter support: polarity and barrier properties. Pflugers Arch 1999; 437:823–830.

64.Swisshelm K, Machl A, Planitzer S, Robertson R, Kubbies M, Hosier S. SEMP1, a senescence-associated cDNA isolated from human mammary epithelial cells, is a member of an epithelial membrane protein superfamily. Gene 1999; 226:285– 295.

65.Peacock RE, Keen TJ, Inglehearn CF. Analysis of a human gene homologous to rat ventral prostate. 1. Protein. Genomics 1997; 46:443–449.

66.Paperna T, Peoples R, Wang YK, Kaplan P, Francke U. Genes for the CPE receptor (CPETR1) and the human homolog of RVP1 (CPETR2) are localized within the Williams-Beuren syndrome deletion. Genomics 1998; 54:453–459.

67.Sirotkin H, Morrow B, Saint-Jore B, Puech A, Das Gupta RPatanjali SR, Skoultchi A, Weissman SM, Kucherlapati R. Identification, characterization, and precise mapping of a human gene encoding a novel membrane-spanning protein from the 22q11 region deleted in velo-cardio-facial syndrome. Genomics 1997; 42:245–251.

68.Chen Z, Zandonatti M, Jakubowski D, Fox HS. Brain capillary endothelial cells express MBEC1, a protein that is related to the Clostridium perfringens enterotoxin receptors. Lab Invest 1998; 78:353–363.

69.Morita K, Sasaki H, Fujimoto K, Furuse M, Tsukita S. Claudin-11/OSP-based tight junctions of myelin sheaths in brain and Sertoli cells in testis. J Cell Biol 1999; 145:579–588.

70.Niimi T, Nagashima K, Ward JM, Minoo P, Zimonjic DBPopescu NC, Kimura S. Claudin-18, a novel downstream target gene for the T/EBP/NKX2.1 homeodomain transcription factor, encodes lungand stomach-specific isoforms through alternative splicing. Mol Cell Biol 2001; 21:7380–7390.

71.Furuse M, Hata M, Furuse K, Yoshida Y, Haratake A, Sugitani Y, Noda T, Kubo A, Tsukita S. Claudin-based tight junctions are crucial for the mammalian epidermal barrier: a lesson from claudin-1-deficient mice. J Cell Biol 2002; 156: 1099–1111.

72.Turksen K, Troy TC. Permeability barrier dysfunction in transgenic mice overexpressing claudin 6. Development 2002; 129:1775–1784.

The classical cadherins have five EC domains, whereas other cadherins may have more than 30 EC domains. E-cadherin, N-cadherin, and P-cad- herin are classical cadherins that have been extensively studied in the context of intercellular adhesion. The high-resolution structure of E-cadherin shows that the first EC domain binds Ca2+ and has an exposed protein surface that may provide homophilic binding specificity (8). X-ray crystallographic studies of N-cadherin show that the EC domains are involved in higherorder protein organization through the formation of dimers with cadherin EC domains on the same cell surface that interact with cadherin dimers on adjacent cells (9). Cells transfected with E-cadherin or P-cadherin preferentially aggregate with cells expressing the same cadherins during cell-sorting experiments (10).

Some cadherin proteins are necessary for the integrity of the retinal photoreceptor sensory cells and the cochlear neurosensory cells. A photo- receptor-specific cadherin (prCAD) was identified by subtractive hybridization of a bovine retina cDNA library and was shown to be localized at the base of the outer segment (11). Mice with a presumptive null mutation of prCAD initially develop normal retinae. However, from 1 to 5 months after birth there is a progressive loss of photoreceptor cells.

Immunocytochemistry experiments suggest that E-cadherin is involved in reticular lamina maintenance in the organ of Corti before the development of fluid spaces in the cochlea (12). In humans, Usher syndrome type 1F (deafness and progressive blindness) is caused by mutations of PCDH15, encoding protocadherin 15 (13,14). Finally, mutations of the cadherin-related 23 gene, CDH23, cause Usher syndrome type 1D, as well as nonsyndromic hearing loss DFNB12, which are the topics of this chapter.

II.CDH23

CDH23 spans more than 250 kb of genomic DNA, with 69 exons encoding a 9–10-kb transcript; three of the exons are alternatively spliced (15,16). The largest CDH23 isoform encodes a deduced 3354-amino-acid protein that is predicted, by TMpred and TMHMM, to have one membrane-spanning region that divides cadherin 23 into a large extracellular domain with 27 EC domains and a cytoplasmic domain of 268 amino acids (15). The extracellular domain contains two alternatively spliced miniexons (16), and the cytoplasmic domain contains one alternatively spliced exon encoding 35 amino acids (15). The cytoplasmic domain of CDH23 is highly conserved among the human, mouse, rat, bovine, and pu erfish homologs, but is unique from the cytoplasmic domains of other cadherin proteins.

III.DFNB12

A ected individuals with nonsyndromic hereditary hearing loss are often clinically indistinguishable. However, genetic linkage studies provide the information necessary to distinguish between di erent hereditary hearing loss loci. In 1996, a new locus for nonsyndromic recessive deafness, DFNB12, was mapped to chromosome 10q21–q22 (17). A ected individuals from families with nonsyndromic deafness, linked to DFNB12, present with prelingual, bilateral, moderate to profound sensorineural hearing loss (SNHL) in the absence of any extra-auditory features (15,17,17a). Clinical evaluations of balance, the attainment of motor developmental milestones, and, when tested, electronystagmography (ENG) with caloric testing are all within normal limits for DFNB12 patients, suggesting normal vestibular function. A ected DFNB12 individuals lack a clinically significant vestibular dysfunction, although partial vestibular deficits may be overlooked without a comprehensive vestibular evaluation. Ocular funduscopy or electroretinography (ERG) of a ected DFNB12 individuals confirms the absence of retinitis pigmentosa (RP).

IV. USH1D

Three clinical subtypes of Usher syndrome (USH) are distinguished on the basis of the auditory, visual, and vestibular phenotypes (18–20). Type 1 USH (USH1) is the most severe subtype and is characterized by congenital profound hearing loss, vestibular areflexia, and onset of RP by age 10. The loci for USH1 (designated USH1A–USH1G) are distinguishable only on the basis of their genetic map location (21). Five USH1 genes have been identified (USH1B, USH1C, USH1D, USH1F, and USH1G) (13–16,22–24,24a).

The USH1D locus was mapped in 1996 to chromosome 10q (25), overlapping the DFNB12 locus. A ected individuals with USH1D have profound SNHL and vestibular areflexia, which is demonstrated by puretone audiometry and a lack of responses to caloric irrigation, respectively. If calorics cannot be performed, a history of delayed motor developmental milestones and abnormal performance in tandem gait and Romberg evaluations are consistent with vestibular areflexia. The onset of retinal degeneration typically presents as nyctalopia during the first decade of life, with progressive loss of peripheral vision, and, in some cases, leads to complete blindness. RP is confirmed by ERG or ocular funduscopy in patients.