Secondary Logo

Journal Logo

Molecular basis of hearing loss associated with enlarged vestibular aqueduct

Yu, Xiaoyua,b,c; Wu, Haoa,b,c,*; Yang, Taoa,b,c,*

doi: 10.1097/JBR.0000000000000032
Review Articles
Open

Enlarged vestibular aqueduct (EVA) is a radiologic malformation of the inner ear most commonly seen in children with sensorineural hearing loss. Most cases of EVA with hearing loss are caused by biallelic mutations of SLC26A4. In this review, we discuss the potential mechanisms underlying the pathogenesis of hearing loss with EVA due to malfunction of SLC26A4, the detection rates of SLC26A4 mutations in EVA patients from different populations, and the role of other genetic factors (eg, mutations in FOXI1 and KCNJ10) as etiologic contributors to EVA. Elucidating the molecular etiology of EVA-associated hearing loss may facilitate genetic counseling and lead to potential therapeutic strategies.

aDepartment of Otorhinolaryngology-Head and Neck Surgery, Shanghai Ninth People's Hospital

bEar Institute, Shanghai Jiao Tong University School of Medicine

cShanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai, China

Corresponding authors: Tao Yang, Ear Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China. E-mail: yangtfxl@sina.com; Hao Wu, Department of Otolaryngology-Head & Neck Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. E-mail: wuhao622@sina.cn

Received 3 January, 2019

Accepted 9 April, 2019

Online date: June 19, 2019

This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0

Back to Top | Article Outline

Clinical features associated with enlarged vestibular aqueduct

Enlarged vestibular aqueduct (EVA) is a radiologic malformation of the inner ear most commonly seen in children with sensorineural hearing loss.[1] First described by Valvassori and Clemis[2] in 1978, the radiological criteria of EVA was defined as the bony vestibular aqueduct exceeding 1.5 mm at the midpoint. Hearing loss with EVA may be associated with other abnormalities as part of a syndrome, or it could be an isolated clinical entity (deafness, autosomal recessive 4 [DFNB4], MIM 600791, or non-syndromic EVA).[3,4] Pendred syndrome (MIM 274600) is the most common syndrome associated with EVA. It is typically characterized by the presence of EVA, sensorineural hearing loss, and defect in thyroid iodine organification, which in some cases may result in goiter in late childhood to early adulthood.[5] EVA has also been observed in branchio-oto-renal syndrome (MIM 113650), Waardenburg syndrome (MIM 606662,193500, 608890, 600193,193510), distal renal tubular acidosis with sensorineural deafness (MIM 267300), and CHARGE syndrome (MIM 214800).[6] EVA may occur either unilaterally or bilaterally and may be accompanied by Mondini dysplasia, an incomplete partition of cochlea. Hearing loss associated with EVA in children is typically congenital or prelingual, usually progressive or fluctuating and variable in severity.[7,8] Some patients may suffer a sudden decrease in hearing after mild barotrauma or head trauma. It seems that the severity of the enlargement of vestibular aqueduct does not correlate with the severity of hearing loss, and the presence of a cochlear malformation is not associated with the degree of hearing loss.[9] Therefore, the dilation of the osseous vestibular aqueduct itself is unlikely the direct cause of hearing impairment in EVA patients.

Back to Top | Article Outline

Pathophysiological mechanisms of EVA with SLC26A4 mutations

Mutations in the gene SLC26A4 (solute carrier family 26 members 4, SLC26A4) are the most prevalent cause of hearing loss associated with EVA and the second most frequent cause of autosomal recessive non-syndromic sensorineural hearing loss in many populations throughout the world.[4,10,11]SLC26A4 encodes a multipass transmembrane protein SLC26A4, also known as pendrin, which is mainly expressed in the thyroid gland, kidney, and inner ear.[12,13] Pendrin functions as a Cl/I transporter at the apical membrane of follicular epithelial cells in the thyroid, where SLC26A4 is expressed at extremely high levels. It mediates the transport of intracellular inorganic iodine into the thyroid follicular lumen (a process called “iodide efflux”) for the thyroid hormone biosynthesis.[14–16] The role of pendrin in iodide efflux appears to correlate with thyroid pathology in individuals affected by Pendred syndrome. In the inner ear, expression of pendrin occurs in non-sensory epithelial cells of the external sulcus region in the cochlea, transitional cells in the saccule and utricle, and in the endolymphatic sac and duct.[17,18] The significant insights into the role of pendrin in hearing and the mechanism of hearing impairment with EVA have been gained using the SLC26A4 knockout (SLC26A4−/−) mouse.[19] The SLC26A4−/− mouse has profound hearing loss and displays signs of vestibular dysfunction. The endolymphatic sac and duct, as well as the entire inner ear of these mice, are dilated, similar to that found radiologically in patients with EVA. Subsequent studies of SLC26A4−/− mice indicate that pendrin functions as a Cl/HCO3 exchanger in the inner ear. At embryonic day (E) 14.5 the cochlea and endolymphatic sac of SLC26A4−/− mice begin to dilate, as the result of the failed onset of pendrin expression in the inner ear at E11.5. Loss of pendrin leads to endolymphatic acidification at postnatal day (P)10, which may inhibit the reabsorption of Ca2+ via acid-sensitive Ca2+ channels. Ca2+ overloading may eventually lead to inhibition of the mechanosensory transduction essential for auditory function and promote the degeneration of hair cells.[20] Moreover, lack of pendrin in SLC26A4−/− mice results in bicarbonate accumulation and alkalization of the intrastrial spaces. The extracellular alkalization in stria vascularis may enhance oxidative stress leading to a loss of KCNJ10 (adenosine triphosphate-sensitive inward rectifier potassium channel 10) protein expression at P15 and failure to establish endocochlear potential, which was thought to play a direct causative role in hearing impairment associated with EVA.[21] Pendrin insufficiency also leads to strial dysfunction and degeneration.[22] More recently, a study demonstrated in vitro that during morphogenesis of the inner ear the endolymphatic sac absorbs fluid in a SLC26A4-dependent manner.[23] The study shows that the mitochondria-rich cells in endolymphatic sacs express various transporters, channels, pumps, and exchangers, among which the chloride-bicarbonate exchanger SLC26A4 plays a critical role in the transport of chloride from endolymph across the apical membrane into the cytosol of the mitochondria-rich cells. Disruption of this mechanism of transepithelial endolymph absorption by endolymphatic sac caused by SLC26A4 mutations might be the root cause of hearing loss associated with EVA.

Back to Top | Article Outline

Detection rates of SLC26A4 mutations in different populations

To date, there have been over 300 SLC26A4 variants identified as causative mutations in individuals affected by non-syndromic EVA or Pendred syndrome. Although non-syndromic EVA and Pendred syndrome are recessively inherited, for many patients molecular testing for the SLC26A4 coding regions and splice sites mutations has failed to identify causative mutations in both alleles.[24–26] The reported detection rates of biallelic and monoallelic SLC26A4 mutations in affected individuals varies among different ethnic groups, ranging from as low as 16% in North American Caucasians to as high as 62% or more in Chinese.[27] A number of studies analyzing SLC26A4 mutations in EVA patients from different districts of China have been reported. In one study from northern China screening SLC26A4 mutations in 107 probands with EVA, two mutant alleles were found in 88.4% of the affected patients, and 1 mutant allele was detected in 9.5%.[28] Another study in Taiwan, China tested SLC26A4 mutations in 101 families with non-syndromic EVA or Pendred syndrome. They detected two mutant alleles in 62% of the families, 1 mutant allele in 24% and no mutation in 14%.[29] Our research group performed mutation analysis of SLC26A4 gene in a clinically well-phenotyped cohort of 140 probands from eastern China. We identified biallelic mutations in 76.4% of patients and monoallelic mutations in 8.6%.[30] In other populations such as North American Caucasians, the detection rate of SLC26A4 is quite low, with nearly 50% of the affected patients having no detectable mutations.[6]

Back to Top | Article Outline

Other genetic contributors to hearing loss with EVA

The inability to identify two mutant alleles of SLC26A4 in individuals with hearing loss associated with EVA suggests the possible involvement of (1) multiexon deletions or duplications in SLC26A4; (2) mutations in the SLC26A4 gene noncoding regions (eg, promoter and intronic mutations); or (3) mutations in other genes that might act in trans in combination with mutations of SLC26A4 to cause hearing loss with EVA. Consistent with these hypothesis, several genomic deletions spanning multiple exons of SLC26A4 have been described previously.[31–33] Most of them are identified in single cases, and multiexon deletions and duplications are estimated to account for approximately 1.8% of missing SLC26A4 mutations in EVA patients overall.[34] In our previous study, a 7666 bp deletion in SLC6A4 gene spanning the first three exon and start codon was identified in a consanguineous family with non-syndromic EVA.[35] The same multiexon deletion was also detected in 4 out of 22 (18%) Chinese probands with non-syndromic EVA carrying 1 mutant allele of SLC26A4. Although multiexon deletions account for a rather low percentage of the overall causes of EVA, clinical testing for multiexon deletions may be warranted for patients with monoallelic SLC26A4 mutations.

Mutations in noncoding regions of SLC26A4 gene also contribute to the pathogenesis of EVA. For instance, mutations in the promoter or enhancer region may decrease gene expression and mutations in the introns of SLC26A4 may create cryptic splice sites. Consistent with this hypothesis, a mutation within the core promoter element of SLC26A4 gene c.-103T→C has been identified.[36] This cis-regulatory element within the SCL26A4 promoter has a unique head-to-head binding motif for FOXI1 (forkhead box I1), a forkhead transcription factor that activates the transcription of SLC26A4 in the endolymphatic sac and duct. The c.-103T→C mutation disrupts the binding of FOXI1 to the SLC26A4 promoter and abolishes FOXI1-mediated transcriptional activation.

Mutations of FOXI1 itself have also been shown to contribute to the disease phenotype. FOXI1–/– mice are profoundly deaf and have abnormality in the inner ear that resembles human EVA. Additionally, the epithelium of endolymphatic duct and sac of FOXI1–/– mice completely lacks the expression of pendrin.[37] Mutation screening in probands with either non-syndromic EVA or Pendred syndrome identified five FOXI1 mutations that led to reduced transcriptional activation ability in six individuals.[36] One of these patients has a double heterozygous inheritance pattern, carrying one single heterozygous mutation in both SLC26A4 and FOXI1.

Mutations in an inward-rectifier potassium channel encoding gene, KCNJ10, have also been causally related to EVA.[38] Studies in SLC26A4−/− mice have shown that in stria vascularis malfunction of pendrin leads to increased oxidative stress and a reduction of KCNJ10 protein expression.[39,40] Since expression of functional KCNJ10 is critical for the generation of the endocochlear potential, which is necessary for hearing,[41] these observations support the hypothesis that mutations of KCNJ10 might be an etiologic contributor to hearing loss associated with EVA. Consistent with this, two patients were identified with segregated heterozygous mutations in both KCNJ10 and SLC26A4 in a study screening 89 patients with non-syndromic EVA or Pendred syndrome carrying monoallelic SLC26A4 mutations.[38] The KCNJ10 p.R348C and p.P194H mutations identified in this study were damaging to channel activity and led to reduced potassium conductance, suggesting a possible digenic interaction between KCNJ10 and SLC26A4 in the etiology of hearing impairment associated with EVA.

The role of FOXI1 and KCNJ10 mutations in hearing loss with EVA, however, seem to be limited, as illustrated by several subsequent studies systematically testing FOXI1 and KCNJ10 mutations in individuals affected by Pendred syndrome or non-syndromic EVA.[29,30,42–44] Overall, possible pathogenic variants in FOXI1 and KCNJ10 were detected in 1.3% and 3.1% EVA patients respectively.[34] In addition, it has been shown that EVA in some families does not segregate in an autosomal recessive pattern,[45] further supporting that hearing loss with EVA is a complex genetic disease.

Back to Top | Article Outline

Conclusions

EVA-associated hearing loss is a relatively common but enigmatic disorder in children. Studies with mouse models indicate that disruption of fluid absorption by endolymphatic sac that depends on Cl/HCO3 exchanger SLC26A4 during morphogenesis of the inner ear might be the root cause of hearing loss with EVA. Although mutations in SLC26A4, FOXI1, and KCNJ10 together account for a large portion of EVA cases, the etiologic basis of hearing loss in patients without SLC26A4, FOXI1 or KCNJ10 mutations remains unknown. Further investigation is needed to elucidate the underlying etiologies of these patients, thereby providing proper genetic counseling and potential interventions to prevent or reverse EVA-associated hearing loss.

Back to Top | Article Outline

Acknowledgments

None.

Back to Top | Article Outline

Author contributions

XY participated in literature retrieval, manuscript drafting and writing of the main part in the manuscript. TY designed and wrote the manuscript. HW reviewed and modified the manuscript. All authors approved the final version of the paper.

Back to Top | Article Outline

Financial support

None.

Back to Top | Article Outline

Conflicts of interest

The authors declare that they have no conflicts of interest.

Back to Top | Article Outline

References

1. Dossena S, Paulmichl M. The Role of Pendrin in Health and Disease: Molecular and Functional Aspects of the SLC26A4 Anion Exchanger. Springer, Cham. 2017.
2. Valvassori GE, Clemis JD. The large vestibular aqueduct syndrome. Laryngoscope 1978; 88:723–728.
3. Koffler T, Ushakov K, Avraham KB. Genetics of hearing loss: syndromic. Otolaryngol Clin North Am 2015; 48:1041–1061.
4. Parker M, Bitner-Glindzicz M. Genetic investigations in childhood deafness. Arch Dis Child 2015; 100:271–278.
5. Ladsous M, Vlaeminck-Guillem V, Dumur V, et al. Analysis of the thyroid phenotype in 42 patients with Pendred syndrome and nonsyndromic enlargement of the vestibular aqueduct. Thyroid 2014; 24:639–648.
6. Griffith AJ, Wangemann P. Hearing loss associated with enlargement of the vestibular aqueduct: mechanistic insights from clinical phenotypes, genotypes, and mouse models. Hear Res 2011; 281:11–17.
7. Kim BG, Roh KJ, Park AY, et al. Early deterioration of residual hearing in patients with SLC26A4 mutations. Laryngoscope 2016; 126:E286–E291.
8. Noordman BJ, van Beeck Calkoen E, Witte B, et al. Prognostic factors for sudden drops in hearing level after minor head injury in patients with an enlarged vestibular aqueduct: a meta-analysis. Otol Neurotol 2015; 36:4–11.
9. King KA, Choi BY, Zalewski C, et al. SLC26A4 genotype, but not cochlear radiologic structure, is correlated with hearing loss in ears with an enlarged vestibular aqueduct. Laryngoscope 2010; 120:384–389.
10. Everett LA, Glaser B, Beck JC, et al. Pendred syndrome is caused by mutations in a putative sulphate transporter gene (PDS). Nat Genet 1997; 17:411–422.
11. Li XC, Everett LA, Lalwani AK, et al. A mutation in PDS causes non-syndromic recessive deafness. Nat Genet 1998; 18:215–217.
12. Shcheynikov N, Ohana E, Muallem S. Properties and function of the solute carrier 26 family of anion transporters. In: Ion Channels and Transporters of Epithelia in Health and Disease. Physiology in Health and Disease (Hamilton K, Devor D, eds). New York, NY: Springer. 2016.
13. Soleimani M. The multiple roles of pendrin in the kidney. Nephrol Dial Transplant 2015; 30:1257–1266.
14. Kopp P. Mutations in the Pendred syndrome (PDS/SLC26A) gene: an increasingly complex phenotypic spectrum from goiter to thyroid hypoplasia. J Clin Endocrinol Metab 2014; 99:67–69.
15. Silveira JC, Kopp PA. Pendrin and anoctamin as mediators of apical iodide efflux in thyroid cells. Curr Opin Endocrinol Diabetes Obes 2015; 22:374–380.
16. Calil-Silveira J, Serrano-Nascimento C, Kopp PA, et al. Iodide excess regulates its own efflux: a possible involvement of pendrin. Am J Physiol Cell Physiol 2016; 310:C576–582.
17. Choi BY, Kim HM, Ito T, et al. Mouse model of enlarged vestibular aqueducts defines temporal requirement of Slc26a4 expression for hearing acquisition. J Clin Invest 2011; 121:4516–4525.
18. Nishio A, Ito T, Cheng H, et al. Slc26a4 expression prevents fluctuation of hearing in a mouse model of large vestibular aqueduct syndrome. Neuroscience 2016; 329:74–82.
19. Everett LA, Belyantseva IA, Noben-Trauth K, et al. Targeted disruption of mouse Pds provides insight about the inner-ear defects encountered in Pendred syndrome. Hum Mol Genet 2001; 10:153–161.
20. Wangemann P, Nakaya K, Wu T, et al. Loss of cochlear HCO3 secretion causes deafness via endolymphatic acidification and inhibition of Ca2+ reabsorption in a Pendred syndrome mouse model. Am J Physiol Renal Physiol 2007; 292:F1345–F1353.
21. Wangemann P, Itza EM, Albrecht B, et al. Loss of KCNJ10 protein expression abolishes endocochlear potential and causes deafness in Pendred syndrome mouse model. BMC Med 2004; 2:30.
22. Ito T, Nishio A, Wangemann P, et al. Progressive irreversible hearing loss is caused by stria vascularis degeneration in an Slc26a4-insufficient mouse model of large vestibular aqueduct syndrome. Neuroscience 2015; 310:188–197.
23. Honda K, Kim SH, Kelly MC, et al. Molecular architecture underlying fluid absorption by the developing inner ear. Elife 2017; 6:e26851.
24. Choi BY, Stewart AK, Madeo AC, et al. Hypo-functional SLC26A4 variants associated with nonsyndromic hearing loss and enlargement of the vestibular aqueduct: genotype-phenotype correlation or coincidental polymorphisms? Hum Mutat 2009; 30:599–608.
25. Rah YC, Kim AR, Koo JW, et al. Audiologic presentation of enlargement of the vestibular aqueduct according to the SLC26A4 genotypes. Laryngoscope 2015; 125:E216–E222.
26. Rose J, Muskett JA, King KA, et al. Hearing loss associated with enlarged vestibular aqueduct and zero or one mutant allele of SLC26A4. Laryngoscope 2017; 127:E238–E243.
27. Tsukada K, Nishio SY, Hattori M, et al. Ethnic-specific spectrum of GJB2 and SLC26A4 mutations: their origin and a literature review. Ann Otol Rhinol Laryngol 2015; 124 Suppl 1:61S–76S.
28. Wang QJ, Zhao YL, Rao SQ, et al. A distinct spectrum of SLC26A4 mutations in patients with enlarged vestibular aqueduct in China. Clin Genet 2007; 72:245–254.
29. Wu CC, Lu YC, Chen PJ, et al. Phenotypic analyses and mutation screening of the SLC26A4 and FOXI1 genes in 101 Taiwanese families with bilateral nonsyndromic enlarged vestibular aqueduct (DFNB4) or Pendred syndrome. Audiol Neurootol 2010; 15:57–66.
30. Chai Y, Huang Z, Tao Z, et al. Molecular etiology of hearing impairment associated with nonsyndromic enlarged vestibular aqueduct in East China. Am J Med Genet A 2013; 161A:2226–2233.
31. Anwar S, Riazuddin S, Ahmed ZM, et al. SLC26A4 mutation spectrum associated with DFNB4 deafness and Pendred's syndrome in Pakistanis. J Hum Genet 2009; 54:266–270.
32. Fagerheim T, Jonsrud C, Laurent C, et al. Causes of hearing impairment in the Norwegian paediatric cochlear implant program. Int J Audiol 2010; 49:596–605.
33. Rendtorff ND, Schrijver I, Lodahl M, et al. SLC26A4 mutation frequency and spectrum in 109 Danish Pendred syndrome/DFNB4 probands and a report of nine novel mutations. Clin Genet 2013; 84:388–391.
34. Pique LM, Brennan ML, Davidson CJ, et al. Mutation analysis of the SLC26A4, FOXI1 and KCNJ10 genes in individuals with congenital hearing loss. PeerJ 2014; 2:e384.
35. Pang X, Chai Y, He L, et al. A 7666-bp genomic deletion is frequent in Chinese Han deaf patients with non-syndromic enlarged vestibular aqueduct but without bi-allelic SLC26A4 mutations. Int J Pediatr Otorhinolaryngol 2015; 79:2248–2252.
36. Yang T, Vidarsson H, Rodrigo-Blomqvist S, et al. Transcriptional control of SLC26A4 is involved in Pendred syndrome and nonsyndromic enlargement of vestibular aqueduct (DFNB4). Am J Hum Genet 2007; 80:1055–1063.
37. Hulander M, Kiernan AE, Blomqvist SR, et al. Lack of pendrin expression leads to deafness and expansion of the endolymphatic compartment in inner ears of Foxi1 null mutant mice. Development 2003; 130:2013–2025.
38. Yang T, Gurrola JG 2nd, Wu H, et al. Mutations of KCNJ10 together with mutations of SLC26A4 cause digenic nonsyndromic hearing loss associated with enlarged vestibular aqueduct syndrome. Am J Hum Genet 2009; 84:651–657.
39. Singh R, Wangemann P. Free radical stress-mediated loss of Kcnj10 protein expression in stria vascularis contributes to deafness in Pendred syndrome mouse model. Am J Physiol Renal Physiol 2008; 294:F139–F148.
40. Rozengurt N, Lopez I, Chiu CS, et al. Time course of inner ear degeneration and deafness in mice lacking the Kir4.1 potassium channel subunit. Hear Res 2003; 177:71–80.
41. Korver AM, Smith RJ, Van Camp G, et al. Congenital hearing loss. Nat Rev Dis Primers 2017; 3:16094.
42. Liu Y, Wang L, Feng Y, et al. A new genetic diagnostic for enlarged vestibular aqueduct based on next-generation sequencing. PLoS One 2016; 11:e0168508.
43. Rehman AU, Friedman TB, Griffith AJ. Unresolved questions regarding human hereditary deafness. Oral Dis 2017; 23:551–558.
44. Zhao J, Yuan Y, Huang S, et al. KCNJ10 may not be a contributor to nonsyndromic enlargement of vestibular aqueduct (NSEVA) in Chinese subjects. PLoS One 2014; 9:e108134.
45. Muskett JA, Chattaraj P, Heneghan JF, et al. Atypical patterns of segregation of familial enlargement of the vestibular aqueduct. Laryngoscope 2016; 126:E240–E247.
Keywords:

enlarged vestibular aqueduct; gene mutation; hearing loss; pathogenesis; SLC26A4

Copyright © 2019 The Chinese Medical Association. Published by Wolters Kluwer Health, Inc.