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Ear and kidney syndromes: Molecular versus clinical approach

2004; Elsevier BV; Volume: 65; Issue: 2 Linguagem: Inglês

10.1111/j.1523-1755.2004.00390.x

1523-1755

Hassane Izzedine, F. Tankéré, Vincent Launay‐Vacher, Gilbert Deray,

Tumors and Oncological Cases

Ear and kidney syndromes: Molecular versus clinical approach.The association between ear and kidney anomalies is not usually due to an insult to the embryo. In recent years, many essential development control genes that coordinate the assembly and function of kidney and ear have been discovered through the generation of animal mutants and have increased our understanding of the mechanisms of human oto-renal diseases. Here, we describe ear and kidney clinical syndromes and their molecular expression. Ear and kidney syndromes: Molecular versus clinical approach. The association between ear and kidney anomalies is not usually due to an insult to the embryo. In recent years, many essential development control genes that coordinate the assembly and function of kidney and ear have been discovered through the generation of animal mutants and have increased our understanding of the mechanisms of human oto-renal diseases. Here, we describe ear and kidney clinical syndromes and their molecular expression. First ear and kidney abnormalities were reported in 1946 by Edith Potter's association of crumpled and flattened ears with bilateral kidney agenesis [1.Potter E.L. Bilateral renal agenesis.J Pediatr. 1946; 29: 68Abstract Full Text PDF PubMed Google Scholar]. Ear malformations are associated with an increased frequency of clinically significant structural renal anomalies compared with the general population. These include specific multiple congenital anomaly syndromes, Townes-Brocks syndrome (TBS), branchio-oto-renal (BOR) syndrome, among others. Many studies in the literature have noted a significant association between renal anomalies and various ear anomalies. Ear pits and tags, perhaps the most common minor ear malformations, occur with a frequency of five to six per 1000 live births [2.Kugelman A. Hadad B. Ben-David J. et al.Preauricular tags and pits in the newborn: the role of hearing tests.Acta Paediatr. 1997; 86: 170-172Crossref PubMed Google Scholar, 3.Kankkunen A. Thiringer K. Hearing impairment in connection with preauricular tags.Acta Paediatr Scand. 1987; 76: 143-146Crossref PubMed Google Scholar]. In the pediatric population, structural renal anomalies occur in one to three per 100 live births [4.Stoll C. Wiesel A. Queisser-Luft A. et al.Evaluation of the prenatal diagnosis of limb reduction deficiencies. EUROSCAN Study Group.Prenat Diagn. 2000; 20: 811-818Crossref PubMed Scopus (44) Google Scholar]. Children who had isolated preauricular tags presented on renal ultrasonography urinary tract abnormalities in 3% to 8% of cases as hydronephrosis, horseshoe kidney, kidney agenesis, or hypoplastia [5.Kohelet D. Arbel E. A prospective search for urinary tract abnormalities in infants with isolated preauricular tags.Pediatrics. 2000; 105: E61Crossref PubMed Google Scholar, 6.Leung A.K. Robson W.L. Association of preauricular sinuses and renal anomalies.Urology. 1992; 40: 259-261Abstract Full Text PDF PubMed Scopus (35) Google Scholar]. A recent study [7.Queisser-Luft A. Stolz G. Wiesel A. et al.Association between renal malformations and abnormally formed ears: Analysis of 32,589 newborns and newborn fetuses of the Mainz Congenital Birth Defect Monitoring System.in: XXI David W Smith Workshop on Malformation and Morphogenesis. 2000: 60Google Scholar] of 32,589 consecutive live births, still births, and abortions over 10 years in the Mainz Congenital Birth Defect Monitoring System noted a 1.2% prevalence of renal anomalies. After patients with syndromic diagnoses were excluded, auricular pits or cup ears and specific renal anomalies were still associated [7.Queisser-Luft A. Stolz G. Wiesel A. et al.Association between renal malformations and abnormally formed ears: Analysis of 32,589 newborns and newborn fetuses of the Mainz Congenital Birth Defect Monitoring System.in: XXI David W Smith Workshop on Malformation and Morphogenesis. 2000: 60Google Scholar]. Half a century later, ear and kidney development has been characterized in great detail, demonstrating that embryologically, ear and kidney primordia arise at different times and develop at different rates Figure 1. Therefore, the association between ear and kidney anomalies is usually not due to an isolated insult to the embryo that would affect both developing structures at the same time. The genes responsible for hereditary deafness in humans and in vertebrate model systems have been recently identified. These serve as useful molecular markers, but more important, a number of these genes undoubtly play key roles in kidney and ear determination. Table 1 summarizes the findings in the various model systems to date. Recent identification of genes that are responsible for BOR syndrom and TBS, along with gene expression studies of these genes, has shown that these genes were expressed in developing ear and kidney structures at different times during morphogenesis [8.Kalatzis V. Sahly I. El-Amraoui A. Petit C. Eya1 expression in the developing ear and kidney: Towards the understanding of the pathogenesis of branchio-oto-renal (BOR) syndrome.Dev Dyn. 1998; 213: 486-499Crossref PubMed Scopus (69) Google Scholar].Table 1Ear and kidney genes' functionsEar and kidney genes' functionsGenesEarKidneyGlial cell-line–derived neutrophic factorProtects hair cells from damageEssential for ureteric bud growth and branching morphogenesis of the ureteric bud epitheliumFibroblast growth factorsInduces both the otic placode and the epithelial organization of the otic vesicleMaintains the nephrogenic mesenchyme; induces its condensation and autocrine secretion of Wnt-4 converts it to epitheliumBone morphogenic proteinsProteins emanating from the otic epithelium influence chondrogenesis of the otic capsule, including the cartilage surrounding the semicircular canalsModulate ureteric bud branching and keep bud development in step with that of other tissue typesWnt signaling and Frizzled receptorsCould be involved in several aspects of late cochlear differentiation and/or auditory functionCritically required for tubulogenesis in the pronephric kidneyGATA3Repressor of critical genes involved in cell differentiation in the organ of cortiIntervenes at the interface of Wolffian duct and the metanephric blastema at about 7 weeks gestational ageParchorinGenerally plays a critical role in water-secreting cells, possibly through the regulation of chlorideionPrestinRequired for electromotility of the outer hair cell and for the cochlear amplifier; the motor protein of the cochlear outer hair cellAtrial natriuretic peptideMay be involved in fluid homeostasis in the inner ear and the kidneyBarttinCrucial for renal salt reabsorption and potassium recycling in the inner earIncreases surface expression and changes current properties of ClC-K channels and is required for adequate tubular salt reabsorptionATP6B1Role in endolymph pH homeostasis and in normal auditory functionRole in normal vectorial acid transport into the urine by the kidney encoding the B-subunit of the apical proton pump mediating distal nephron acid secretionGyroIntervenes on renal excretion of phosphate, and impairment of Na+/phosphate cotransport by renal brush-border membrane vesiclesKCNQMay be present in amniote vestibular hair cells; destabilization of the resting potential and increase in [Ca2+]i, as may result from impaired KCNQ4 function in IHCs, whereas mutations in KCNQ1 causes deafness by affecting endolymph secretion, the mechanism leading to KCNQ4-related hearing loss is intrinsic to outer hair cellsAQP-2Role in the development of endolymph homeostasisRegulated urinary diluting ability; important for rapid near-isosmolar transepithelial fluid absorption/secretion and for rapid vectorial water movement driven by osmotic gradientsMpv17Peroxisomal protein involved in the metabolism of reactive oxygen species; the severe sensorineural hearing loss and degenerative changes of the cochlear structures indicate that cochlear structures, especially the outer hair cells and the intermediate cells of the stria vascularis, are vulnerable to the missing Mpv17 gene product; both organs have specialized epithelia involved in active ion transport, which are separated from the vessels by a basement membrane of similar composition; glomerular and the stria vascularis basement membrane are simultaneously affected in early stages Open table in a new tab The ear is the organ of hearing and balance and consists of three parts: the outer ear, the middle ear, and the inner ear. The outer ear and middle ear are the apparatus for the collection and transmission of sound. The inner ear is responsible for analyzing sound waves, and also contains the mechanism by which the body keeps its balance. The outer ear is comprised of the pinna and ear canal; the middle ear includes the eardrum, hammer, anvil, stirrup, and eustachian tube; and the inner ear includes the vestibule, semicircular canals, and cochlea. Sensory impulses from the inner ear pass to the brain via the vestibulocochlear nerve. The outer ear consisting of the pinna (also called the auricle) is the visible part of the ear and is composed of folds of skin and cartilage. The pinna leads into the ear canal (also called the meatus) and is about 1 inch (or 2.5 cm) long in adults and closed at its inner end by the tympanic membrane or (eardrum). The part of the canal nearest the outside is made of cartilage. The cartilage is covered with skin that produces wax, and the tiny hairs in the canal traps dust, pollen, pollution, and small foreign bodies. The middle ear is a small cavity between the eardrum and the inner ear. It conducts sound to the inner ear by means of a chain of three tiny, linked, movable bones called ossicles. They link the eardrum to an oval window in the bony wall on the opposite inner side of the middle ear cavity. The bones are named because of their shapes. The malleus, or hammer, is joined to the inside of the eardrum. The incus, or anvil, has one broad joint with the malleus (which lies almost parallel to it) and a delicate joint to the third bone, the stapes, or stirrup. The base of the stapes fills the oval window, which leads to the inner ear. The middle ear is cut off from the outside by the eardrum, but it is not completely airtight. A ventilation passage, called the eustachian tube, runs forward and down into the back of the nose. The eustachian tube is normally closed, but it opens by muscular contraction when yawning and swallowing. The middle ear acts as a transformer. It passes the vibrations of sound from compression and decompression of the outside air. The air is a thin medium that carries the sound into the inner ear where the fluid in the inner ear, a thicker medium, resonates the sound vibration. The inner ear is an extremely intricate series of structures contained deep within the bones of the skull. It consists of a maze of winding passageways, collectively known as the labyrinth. The front part, the cochlea, is a tube resembling a snail's shell and is related to hearing. The rear part, which is three semicircular canals and two other organs, is concerned with balance. The semicircular canals are set at right angles to each other and are connected to a cavity known as the vestibule. These canals contain hair cells bathed in fluid. Some of these cells are sensitive to gravity and acceleration and others respond to head positions and movement (side to side, up and down, or tilted). Posture or direction information is registered by the relevant cells and conveyed by nerve fibers to the brain. The ear is susceptible to a large number of disorders, some of which can lead to deafness. The embryogenesis of the association of renal and auricular anomalies is unclear. The combination of ear and kidney anomalies in the early stages of development can be explained on the assumption that mesodermal induction (transcription factor, gene expression) is responsible for normal differentiation of both organs. However, in the late stages of development, those factors only intervene in the inner ear function Figure 2. Organogenesis involves many cellular processes, such as proliferation, cell adhesion, apoptosis, cell differentiation, cell migration, all of which require molecules from different classes and family. In recent years, many essential developmental control genes that coordinate the assembly and function of kidney and ear have been discovered through the generation of animal mutants and have increased our understanding of the mechanisms of epithelial interactions. Transcription factors, growth factors, and their receptors that are essential for both ear and kidney development are discussed and their functions and phenotype are summarized in Tables 1 and 2, respectively:Table 2Ear and kidney syndromesDevelopmental impactLesionsGenes, gene products, and chromosomeEarKidneyEarKidneyClinical syndromePax-Six-Eya-DatchPreplacode otic ectoderm; neuroepithelia of inner earMetanephrogenic mesenchyme; urogenital ridge; ureteric bud outgrowthHearing loss; cervical fistulas and cysts; preauricular pits and appendages; auricular malformations; atresia to stenosis of the external auditory canal; underdeveloped cochlea and semicircular canalsCollecting system duplications; renal hypoplasia; cystic dysplasia and agenesis; hydronephrosis; ureteropelvic junction obstruction; vesicoureteral reflux; glomerular hyalinization; mesangial proliferation; basement membrane splittingBranchio-oto-renal (BOR) syndromeSALL1 Chr 16q12.1Later steps in development of the outer, middle and inner ear; differenciation of the otic vesicleOutgrowth of the urorectal septum; metanephric mesenchymeExternal ear anomalies; hearing lossDysplastic kidneys or agenesis; horseshoe kidney; multicystic kidney; posterior urethral valves; Vesicoureteral reflux; renal failureTownes-Brocks syndrome (TBS)Anosmin1 Chr Xp22.3Inner earMesonephric tubules and duct; branches of ureteric budHearing lossRenal aplasia; absent development or early degeneration of the collecting duct systemKalmann syndromeBarttin Chr 1p31Stria vascularis (K+ secreting marginal cells); K+ secreting vestibular dark cellsStria vascularis; thick ascending limb; basolateral membranes of intercalated cells of the collecting ductSensorineural deafnessRenal failure; diabetes insipidus; renal salt wastingBartter sensorineural deafness (BSND) syndromePendrin Chr 7q31Inner earApical membrane of intercalated cells in the cortical renal collecting ductDevelopmental abnormalities of the cochlea; sensorineural hearing lossAcid-base disturbances?Pendrin syndromeMYH9 geneInner earGlomeruliSensorineural hearing lossNephritis; proteinuria; hematuriaFechtner syndromeATP6B1 geneCochlea and endolymphatic sacEncodes the B subunit of the apical proton pump mediating distal nephron acid secretionSensorineural hearing lossSevere hyperchloraemic metabolic acidosis in childhood; hypokalaemia; decreased urinary calcium solubility,Autosomal-recessive distal renal tubular acidosisFibroblast growth factor Chr11qEndolymphatic appendage; otic placode; regulates pillar cell developmentAll nephron; all tubular duct; in cortex and outer medulla; smooth muscle of renal arteriesSevere ear malformationsRenal tubular dysfunction?; small kidney; less ureteric bud branches and nephrons?IntegrinApical hair cells surface stereocillia maturationUreteric bud induction; metanephric mesenchym; mesenchymal-epithelial transitionSensorineural hearing loss,Recurrent hematuria; ultrastructural changes of the glomerular basement membrane; renal failureAlport diseaseForkhead (FKHL) Chr 5q34Otic vesicle; cochlea; vestibulumLater stages of kidney developmentInner ear malformationsNo kidney dysfunction?“Common cavity” phenotypeMegalin Chr 2q24-q31Inner earGlomeruli; proximal renal tubuleHearing lossTubular resorption deficiency with excretion of low molecular proteins; Fanconi syndrome?Nephro and ototoxicity of antibioticsNa/Pi cotransporters PHEX Chr Xp22.2-p22.1Inner earBrush-border membrane of renal proximal tubular cellsInner ear abnormalities; deafness; hearing lossHypophosphatemia; kidney stoneX-linked hypophosphatemiaBone morphogenic protein (BMP4) Chr 14q22-q23Otic epithelium of inner ear; otic capsule; cartilage of semicircular canalsMetanephros ureteric branching morphogenesis; periureteric smooth muscle layer and ureteric elongation?Hypo/dysplastic kidney; hypoureter; ectopic uretrovesical junction; double collecting duct?Wnt4 Chr 1p35Inner earDistal collecting duct epithelium; tubulogenesis; mesenchyme-to-epithelium transformationOtic malformationsAbnormal development of the kidney; failure of kidney-tubule formation; renal fibrosis?GATA3 Chr 10p15Otic vesicleBranching morphogenesis; ureteric bud; collecting duct system; mesangial cellsSensorineural deafnessRenal malformationsHypoparathyroïdism, sensorineural deafness, and renal anomalies (HDR) syndrome Open table in a new tab A number of transcription factors are expressed in the presumptive otic ectoderm, but two of the earliest genes activated in the presumptive otic ectoderm are the transcriptional regulators Pax8 (OMIM 167415) and Pax2 (OMIM 167409) [9.Groves A.K. Bronner-Fraser M. Competence, specification and commitment in otic placode induction.Development. 2000; 127: 3489-3499PubMed Google Scholar, 10.Heller N. Brandli A.W. Xenopus Pax-2/5/8 orthologues: novel insights into Pax gene evolution and identification of Pax-8 as the earliest marker for otic and pronephric cell lineages.Dev Genet. 1999; 24: 208-219Crossref PubMed Scopus (119) Google Scholar, 11.Pfeffer P.L. Gerster T. Lun K. et al.Characterization of three novel members of the zebrafish Pax2/5/8 family: Dependency of Pax5 and Pax8 expression on the Pax2.1 (noi) function.Development. 1998; 125: 3063-3074PubMed Google Scholar]. Other transcriptional regulators expressed in preplacode otic ectoderm include members of the Six, Eya, and Dach gene families, defined as a Pax-Six-Eya-Dach synergistic regulatory network involved in the formation of a number of organs. Metanephric kidney development begins with the formation of the metanephrogenic mesenchyme; this event depends on the prior action in the intermediate mesoderm of transcription factors such as Pax2 and Eya1. Six1 (OMIM 601205) and Six4 (OMIM 606342) are expressed in the developing inner ear. Expression of Six genes is also seen in the individual otic placodes in the Xenopus, chick, and mouse [12.Ohto H. Kamada S. Tago K. et al.Cooperation of six and eya in activation of their target genes through nuclear translocation of Eya.Mol Cell Biol. 1999; 19: 6815-6824Crossref PubMed Google Scholar, 13.Esteve P. Bovolenta P. cSix4, a member of the six gene family of transcription factors, is expressed during placode and somite development.Mech Dev. 1999; 85: 161-165Crossref PubMed Scopus (71) Google Scholar, 14.Ozaki H. Yamada K. Kobayashi M. et al.Structure and chromosome mapping of the human SIX4 and murine Six4 genes.Cytogenet Cell Genet. 1999; 87: 108-112Crossref PubMed Google Scholar, 15.Kobayashi M. Osanai H. Kawakami K. Yamamoto M. Expression of three zebrafish Six4 genes in the cranial sensory placodes and the developing somites.Mech Dev. 2000; 98: 151-155Crossref PubMed Scopus (66) Google Scholar, 16.Ghanbari H. Seo H.C. Fjose A. Brandli A.W. Molecular cloning and embryonic expression of Xenopus Six homeobox genes.Mech Dev. 2001; 101: 271-277Crossref PubMed Scopus (95) Google Scholar]. In the embryonic human kidney, the EYA1 gene is expressed strongly, and in the BOR syndrome there is an inductive fault between the ureteric bud and the metanephric mesenchymal mass as the ureteric bud branches into the renal parenchyma. Eya4 is also thought to have a role in ear formation, as its expression has been reported in neuroepithelia of rat inner ear from E14.5 onwards, and loss of Eya4 in humans causes deafness [17.Borsani G. DeGrandi A. Ballabio A. et al.EYA4, a novel vertebrate gene related to Drosophila eyes absent.Hum Mol Genet. 1999; 8: 11-23Crossref PubMed Scopus (95) Google Scholar, 18.Wayne S. Robertson N.G. DeClau F. et al.Mutations in the transcriptional activator EYA4 cause late-onset deafness at the DFNA10 locus.Hum Mol Genet. 2001; 10: 195-200Crossref PubMed Google Scholar]. Dach proteins (OMIM 603803) have shown to have direct protein-protein interactions with Eya family members [19.Heanue T.A. Reshef R. Davis R.J. et al.Synergistic regulation of vertebrate muscle development by Dach2, Eya2, and Six1, homologs of genes required for Drosophila eye formation.Genes Dev. 1999; 13: 3231-3243Crossref PubMed Scopus (265) Google Scholar] and epistatic analyses in Drosophila have positioned dachshund (dach)—the Drosophila homologue of the vertebrate Dach genes—downstream of eya. During ear development, Dach1 overlaps with Eya1 and Pax2 expression but Dach1 expression does not depend on these genes, as its early expression is not affected in the null mutants. Glial cell-line–derived neutrophic factor (GDNF) encodes a member of the transforming growth factor-β (TGF-β) family of signaling molecules, which has an important role in ureteric-bud induction. Its loss in gdnf-knockout mice leads to the failure of ureteric-bud formation [20.Vainio S. Lin Y. Coordinating early kidney development: Lessons from gene targeting.Nat Rev Genet. 2002; 3: 533-543Crossref PubMed Scopus (147) Google Scholar]. Sall1 is a mammalian homologue of the Drosophilia region-specific homeotic gene splat. Sall1 is expressed in the kidney mesenchyme and its inactivation leads to incomplete ureteric-bud growth and to the failure of tubule formation [21.Cancilla B. Davies A. Cauchi J.A. et al.Fibroblast growth factor receptors and their ligands in the adult rat kidney.KidneyInt. 2001; 60: 147-155Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. Heterozygous SALL1 mutations in humans lead to TBS. Fibroblast growth factor (FGF) receptors (FGFRs) were localized to all nephron and collecting duct epithelia. FGFR-1 and FGFR-3 were localized to glomeruli, FGFR-3 to proximal tubules and FGFR-1 to thin limbs. FGFR-1 through FGFR-3 was localized to distal straight tubules, with FGFR-1 and FGFR-3 localized to distal convoluted tubules. FGFR-1 and FGFR-3 were localized to medullary collecting ducts. In addition, FGFR-1 was localized to the smooth muscle of renal arteries. All FGFR variants were expressed in the cortex and outer medulla, with fewer FGFRs in the inner medulla. FGF-1, FGF-2, FGF-7, FGF-8, and FGF-9 were expressed in the kidney, with FGF-10 expression found only in the cortex. [21.Cancilla B. Davies A. Cauchi J.A. et al.Fibroblast growth factor receptors and their ligands in the adult rat kidney.KidneyInt. 2001; 60: 147-155Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. Experiments by Represa et al[22.Represa J. Leon Y. Miner C. Giraldez F. The int-2 proto-oncogene is responsible for induction of the inner ear.Nature. 1991; 353: 561-563Crossref PubMed Google Scholar] implicated FGFs as having an important early role in ear formation. Depletion of Fgf3 in explants by antisense nucleotides and antibodies prevented the formation of ear vesicles, whereas the application of Fgf2 was shown to rescue otic vesicle induction in explants where the hindbrain had been removed. A later role for Fgf3 signaling in inner ear formation was postulated given that homozygous Fgf3 knockout mice had severe ear malformations where the endolymphatic duct failed to form correctly but still formed ear vesicles [23.Mansour S.L. Goddard J.M. Capecchi M.R. Mice homozygous for a targeted disruption of the proto-oncogene int-2 have developmental defects in the tail and inner ear.Development. 1993; 117: 13-28PubMed Google Scholar]. Very recently, Dode et al[24.Dode C. Levilliers J. Dupont J.M. et al.Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome.Nat Genet. 2003; 33: 463-465Crossref PubMed Scopus (448) Google Scholar] established that loss-of-function mutations in FGFR-1 underlie KAL2 whereas a gain-of-function mutation in FGFR-1 has been shown to cause a form of craniosynostosis. Bone morphogenic proteins (BMP) have recently emerged as likely regulators of development of the permanent kidney (metanephros). Transcripts for BMPs and their receptors have been localized in the developing metanephros, but BMP7 is the only Bmp that is expressed in the nephrogenic mesenchyme [20.Vainio S. Lin Y. Coordinating early kidney development: Lessons from gene targeting.Nat Rev Genet. 2002; 3: 533-543Crossref PubMed Scopus (147) Google Scholar]. In vitro, BMP2, 4, and 7 have direct or indirect roles in regulation of ureteric branching morphogenesis and branch formation. In vivo, renal phenotypes have been reported in BMP7 homozygous null mutant mice and BMP4 heterozygous null mutant mice. In vitro, high concentrations of BMP4 inhibited branching of the ureteric epithelium and changed its morphology, while nephrogenesis was inhibited by 50% [25.Martinez G. Mishina Y. Bertram J.F. BMPs and BMP receptors in mouse metanephric development: In vivo and in vitro studies.Int J Dev Biol. 2002; 46: 525-533PubMed Google Scholar]. BMP4 (OMIM 112262) may be a physiologic regulator of the development of the periureteric smooth muscle layer and ureteric elongation. [26.Raatikainen-Ahokas A. Hytonen M. Tenhunen A. et al.BMP-4 affects the differentiation of metanephric mesenchyme and reveals an early anterior-posterior axis of the embryonic kidney.Dev Dyn. 2000; 217: 146-158Crossref PubMed Scopus (100) Google Scholar]. Furthermore, BMP4 predominantly inhibits neural differenciation in early development. The vertebrate inner ear consists of a complex labyrinth of epithelial cells that is surrounded by a bony capsule. BMP proteins are important for the development of the otic epithelium in the chicken inner ear and possibly acting through BMP receptors IB (BMPRIB) are important for otic capsule formation. In addition, BMPs and their receptors influence chondrogenesis of the otic capsule, including the cartilage surrounding the semicircular canals [27.Chang W. ten Dijke P. Wu D.K. BMP pathways are involved in otic capsule formation and epithelial-mesenchymal signaling in the developing chicken inner ear.Dev Biol. 2002; 251: 380-394Crossref PubMed Scopus (0) Google Scholar]. Wnts are a large family of secreted signal that regulate key morphogenetic steps during embryogenesis. Frizzled proteins have been identified as likely receptors for Wnt ligands in vertebrates and invertebrates. Wnt-4 (OMIM 603490) is critical for genitourinary development but found only in the most distal collecting duct epithelium in the normal murine adult kidney. Wnt-4 expression coincided with mesenchyme-to-epithelium transformation. In the metanephric kidney, Wnt-4 is critically required for tubulogenesis in the pronephric kidney [28.Saulnier D.M. Ghanbari H. Brandli A.W. Essential function of Wnt-4 for tubulogenesis in the Xenopus pronephric kidney.Dev Biol. 2002; 248: 13-28Crossref PubMed Scopus (60) Google Scholar]. 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Roose J. et al.Differential expression of the Groucho-related genes 4 and 5 during early development of Xenopus laevis.Mech Dev. 2000; 91: 311-315Crossref PubMed Scopus (38) Google Scholar, 33.Stark M.R. Rao M.S. Schoenwolf G.C. et al.Frizzled-4 expression during chick kidney development.Mech Dev. 2000; 98: 121-125Crossref PubMed Scopus (14) Google Scholar]. Wnt-4 and frizzled gene families are in the postnatal rat cochlea [34.Daudet N. Ripoll C. Moles J.P. Rebillard G. Expression of members of Wnt and Frizzled gene families in the postnatal rat cochlea.Brain Res Mol Brain Res. 2002; 105: 98-107Crossref PubMed Scopus (16) Google Scholar]. Recently, a member of the GATA-binding family of transcription factors was shown to be involved in the human hypoparathyroidism, sensorineural deafness and renal anomalies (HDR) syndrome. The HDR phenotype is consistent with the expression pattern of GATA3 during human and mouse embryogenesis in the developing kidney (ureteric bud, collecting duct system, and mesangial cells), otic vesicle, and parathyroids. Terminal deletions of chromosome 10p result in that those studies in patients with 10p deletions have defined two nonoverlapping regions that contribute to the complex phenotype (includes hypoparathyroidism, heart defects, immune deficiency, deafness, and renal malformations or DiGeorge-like syndrome). These are the DiGeorge critical region II, which is located on 10p13-14, and the region for the HDR syndrome (Mendelian Inheritance in Man number 146255), which is located more telomeric (10p14-10pter) [35.Van Esch H. Groenen P. Nesbit M.A. et al.GATA3 haplo-insufficiency causes human HDR syndrome.Nature. 2000; 406: 419-422Crossref PubMed Scopus (267) Google Scholar]. The apparently selective GATA3 is further expressed in the developing spiral sensory neurons [36.Rivolta M.N. Holley M.C. GATA3 is downr