Loss of cochlear HCO3−secretion causes deafness via endolymphatic acidification and inhibition of Ca2+reabsorption in a Pendred syndrome mouse model

Wangemann, Philine; Nakaya, Kazuhiro; Wu, Tao; Maganti, Rajanikanth J; Itza, Erin M.; Sanneman, Joel D.; Harbidge, Donald G.; Billings, Sara E.; Marcus, Daniel C.

doi:10.1152/ajprenal.00487.2006

Cited by 226 publications

(256 citation statements)

References 49 publications

(66 reference statements)

Supporting

Mentioning

245

Contrasting

Unclassified

Order By: Relevance

“…The SLC26A4 gene encodes an anion transporter transmembrane protein, pendrin, which is expressed in the thyroid, kidney and cochlea (20). In the inner ear, pendrin is responsible for the exchange of anions, including Cl -and HCO 3 -to maintain the anion composition of endolymph (21). The malfunction of pendrin causes an increase in endolymph volume, which leads to the degeneration of inner ear sensory cells (22).…”

Section: Introductionmentioning

confidence: 99%

Prevalence and range of GJB2 and SLC26A4 mutations in patients with autosomal recessive non-syndromic hearing loss

Jiang

Chen

Shan

et al. 2014

Molecular Medicine Reports

View full text Add to dashboard Cite

Abstract. The frequency and distribution of genetic mutations that cause deafness differ significantly according to ethnic group and region. Zhejiang is a province in the southeast of China, with an exceptional racial composition of the population caused by mass migration in ancient China. The purpose of the present study was to investigate the prevalence and spectrum of gap junction-β2 (GJB2), solute carrier family 26 (anion exchanger) member 4 (SLC26A4) and GJB3 mutations in patients with autosomal recessive non-syndromic hearing loss (ARNHL) in this area. A total of 176 unrelated pediatric patients with ARNHL were enrolled in the study. A genomic DNA sample was extracted from the peripheral blood. Polymerase chain reaction was employed, and the products were sequenced to screen for mutations in GJB2. In addition, a SNaPshot sequencing method was utilized to detect four hotspot mutations in SLC26A4 (IVS7-2A>G and c.2168A>G) and GJB3 (c.538C>T and c.547G>A). All patients were subjected to a temporal bone computed tomography scan to identify enlarged vestibular aqueducts (EVA). In total, 14 different mutations, including two new mutations (p.W44L and p.D66N) of GJB2, were detected. The most common pathogenic mutation of GJB2 was c.235delC (15.1%), followed by c.176_191del16 (1.7%), c.299_300delAT (1.7%), c.508_511dup (0.85%) and c.35delG (0.28%) of the total alleles. Mutation analysis of SLC26A4 demonstrated that 13.6% (24/176) of patients carried at least one mutant allele. The patients with EVA (84.2%) had SLC26A4 mutations, and 31% had homozygous mutations. Only one patient carried a heterozygous mutation of GJB3 (c.538C>T). Compared with the other regions of China, in the present population cohort, the prevalence and spectrum of mutations in GJB2 was unique, and in patients with EVA the frequency of a homozygous mutation in SLC26A4 was significantly lower. These findings may be of benefit in genetic counseling and risk assessment for families from this area of China.

show abstract

Section: Introductionmentioning

confidence: 99%

Prevalence and range of GJB2 and SLC26A4 mutations in patients with autosomal recessive non-syndromic hearing loss

Jiang

Chen

Shan

et al. 2014

Molecular Medicine Reports

View full text Add to dashboard Cite

show abstract

“…1 Functional analysis showed pendrin is an apical transporter of iodide in thyroid cells, 4,5 and it is likely to mediate secretion of HCO 3 -into the endolymph in the cochlea. 6 Pendrin also mediates chloride/base exchange in the kidney cortex. 7 Following the identification of the SLC26A4 gene, the mutations in SLC26A4 causing PS and non-syndromic EVA began to be characterized and more than one hundred mutant alleles have now been identified, mostly missense mutations.…”

Section: Introductionmentioning

confidence: 99%

A mutational analysis of the SLC26A4 gene in Spanish hearing-impaired families provides new insights into the genetic causes of Pendred syndrome and DFNB4 hearing loss.

et al. 2008

View full text Add to dashboard Cite

Pendred syndrome (PS) and DFNB4, a non-syndromic sensorineural hearing loss with enlargement of the vestibular aqueduct (EVA), are caused by mutations in the SLC26A4 gene. Both disorders are recessive, and yet only one mutated SLC26A4 allele, or no mutations, are identified in many cases. Here we present the genetic characterization of 105 Spanish patients from 47 families with PS or non-syndromic EVA and 20 families with recessive non-syndromic hearing loss, which segregated with the DFNB4 locus. In this cohort, two causative SLC26A4 mutations could be characterized in 18 families (27%), whereas a single mutated allele was found in a patient with unilateral hearing loss and EVA in the same ear. In all, 24 different causative mutations were identified, including eight novel mutations. The novel p.Q514K variant was the most prevalent mutation in SLC26A4, accounting for 17% (6/36) of the mutated alleles identified in this study, deriving from a founder effect. We also characterized a novel multiexon 14 kb deletion spanning from intron 3 to intron 6 (g.8091T_22145Cdel). This study also revealed the first case of a de novo recessive mutation p.Q413P causing PS that arose in the proband's paternal allele, the maternal one carrying the p.L445W. The relevance of our results for genetic diagnosis of PS and non-syndromic EVA hearing loss is discussed.

show abstract

“…Pendrin seems to be responsible for the efflux of iodide in thyrocytes (9)(10)(11), and for mediating Cl Ϫ /HCO 3 Ϫ exchange in the kidney cortex (12) and inner ear. In the latter, pendrin is involved in the conditioning of endolymphatic fluid, presumably because of HCO 3 Ϫ secretion (13), thereby modifying inner ear acid-base homeostasis. A variable feature of PS is the development of goitre (apparent in only about 50% of the affected individuals).…”

mentioning

confidence: 99%

Functional assessment of allelic variants in the SLC26A4 gene involved in Pendred syndrome and nonsyndromic EVA

Pera

Dossena

Rodighiero³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

104

View full text Add to dashboard Cite

Pendred syndrome is an autosomal recessive disorder characterized by sensorineural hearing loss, with malformations of the inner ear, ranging from enlarged vestibular aqueduct (EVA) to Mondini malformation, and deficient iodide organification in the thyroid gland. Nonsyndromic EVA (ns-EVA) is a separate type of sensorineural hearing loss showing normal thyroid function. Both Pendred syndrome and ns-EVA seem to be linked to the malfunction of pendrin (SLC26A4), a membrane transporter able to exchange anions between the cytosol and extracellular fluid. In the past, the pathogenicity of SLC26A4 missense mutations were assumed if the mutations fulfilled two criteria: low incidence of the mutation in the control population and substitution of evolutionary conserved amino acids. Here we show that these criteria are insufficient to make meaningful predictions about the effect of these SLC26A4 variants on the pendrin-induced ion transport. Furthermore, we functionally characterized 10 missense mutations within the SLC26A4 ORF, and consistently found that on the protein level, an addition or omission of a proline or a charged amino acid in the SLC26A4 sequence is detrimental to its function. These types of changes may be adequate for predicting SLC26A4 functionality in the absence of direct functional tests.ion transport physiology ͉ genotype-phenotype correlation P endred syndrome (PS) (OMIM#274600) (1) is an autosomal recessive disorder characterized by sensorineural hearing loss (SNHL) and malformations of the inner ear, ranging from enlarged vestibular aqueduct (EVA) (2) to Mondini malformation (3), combined with deficient iodide organification in the thyroid gland, as demonstrated by the positive perchlorate discharge test in affected individuals (4-7). Another form of SNHL associated with EVA, however, showing normal thyroid function, is called nonsyndromic EVA (ns-EVA) (OMIM#600791). The clinical features of PS are the consequence of impaired pendrin function (1), a protein encoded by the SLC26A4 gene (NM 000441). It is a member of the multifunctional anion transporter family SLC26, which mediates the exchange of anions including Cl Ϫ , HCO 3 Ϫ , OH Ϫ , I Ϫ , or formate (8). Pendrin seems to be responsible for the efflux of iodide in thyrocytes (9-11), and for mediating Cl Ϫ /HCO 3 Ϫ exchange in the kidney cortex (12) and inner ear. In the latter, pendrin is involved in the conditioning of endolymphatic fluid, presumably because of HCO 3 Ϫ secretion (13), thereby modifying inner ear acid-base homeostasis. A variable feature of PS is the development of goitre (apparent in only about 50% of the affected individuals). At the thyroid level, the role of pendrin is not conclusive. The transporter could act as an iodide transporter at the apical membrane of thyroid cells and impaired function could therefore lead to the iodide organification defect observed in PS patients (10,11,(14)(15)(16). PS seems to be linked to bi-allelic mutations of the SLC26A4 genes. ns-EVA is genetically more heterogeneous relative to PS, and a...

show abstract

Loss of cochlear HCO₃⁻secretion causes deafness via endolymphatic acidification and inhibition of Ca²⁺reabsorption in a Pendred syndrome mouse model

Cited by 226 publications

References 49 publications

Prevalence and range of GJB2 and SLC26A4 mutations in patients with autosomal recessive non-syndromic hearing loss

Prevalence and range of GJB2 and SLC26A4 mutations in patients with autosomal recessive non-syndromic hearing loss

A mutational analysis of the SLC26A4 gene in Spanish hearing-impaired families provides new insights into the genetic causes of Pendred syndrome and DFNB4 hearing loss.

Functional assessment of allelic variants in the SLC26A4 gene involved in Pendred syndrome and nonsyndromic EVA

Contact Info

Product

Resources

About