Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Am J Hum Genet
2009 May 01;845:651-7. doi: 10.1016/j.ajhg.2009.04.014.
Show Gene links
Show Anatomy links
Mutations of KCNJ10 together with mutations of SLC26A4 cause digenic nonsyndromic hearing loss associated with enlarged vestibular aqueduct syndrome.
Yang T
,
Gurrola JG
,
Wu H
,
Chiu SM
,
Wangemann P
,
Snyder PM
,
Smith RJ
.
???displayArticle.abstract???
Mutations in SLC26A4 cause nonsyndromic hearing loss associated with an enlarged vestibular aqueduct (EVA, also known as DFNB4) and Pendred syndrome (PS), the most common type of autosomal-recessive syndromic deafness. In many patients with an EVA/PS phenotype, mutation screening of SLC26A4 fails to identify two disease-causing allele variants. That a sizable fraction of patients carry only one SLC26A4 mutation suggests that EVA/PS is a complex disease involving other genetic factors. Here, we show that mutations in the inwardly rectifying K(+) channel gene KCNJ10 are associated with nonsyndromic hearing loss in carriers of SLC26A4 mutations with an EVA/PS phenotype. In probands from two families, we identified double heterozygosity in affected individuals. These persons carried single mutations in both SLC26A4 and KCNJ10. The identified SLC26A4 mutations have been previously implicated in EVA/PS, and the KCNJ10 mutations reduce K(+) conductance activity, which is critical for generating and maintaining the endocochlear potential. In addition, we show that haploinsufficiency of Slc26a4 in the Slc26a4(+/-) mouse mutant results in reduced protein expression of Kcnj10 in the stria vascularis of the inner ear. Our results link KCNJ10 mutations with EVA/PS and provide further support for the model of EVA/PS as a multigenic complex disease.
Figure 1
Double Heterozygosity for Mutations in KCNJ10 and SLC26A4 in Family 82120 with EVA/PS
(A) Pedigree and genotypes of the family, showing that the parents and their unaffected child carry a single mutation in either SLC26A4 or KCNJ10 and that the affected child carries both mutations.
(B) Representative chromatograms of the SLC26A4 c.919-2A→G and KCNJ10 p.R348C mutations identified in this family.
Figure 2
Voltage-Clamp Analysis of K+ Conductance of WT and Mutant KCNJ10
(A) Representative trace of current (top) and voltage commands (bottom) versus time in Xenopus oocyte expressing WT KCNJ10. A 1 mM final concentration of channel blocker BaCl2 was added into the extracellular bath at the time point near 20 s, as indicated (black bar).
(B) Steady-state current-voltage relationship for WT and mutant KCNJ10 (mean ± SE, n = 6). For clarity, error bars are shown only for WT and R348C mutant KCNJ10. The differences between the currents of WT and mutant KCNJ10 are statistically significant at voltages between −120 mV and −20 mV (p < 0.05), as indicated by asterisks. The slopes of the current-voltage relationship in the linear range between −120 mV and 0 mV were calculated by linear regression analysis and are shown at the right of each curve (from top: WT, R348C, and P194H; R2 values are shown in parentheses).
Figure 3
Quantitative Immunoblot Analysis of Kcnj10 Expression in Mouse Stria Vascularis
(A) Representative immunoblot showing protein expression of Kcnj10 and β-tubulin in equal sample volumes from Slc26a4+/+, Slc26a4+/−, and Slc26a4−/− mice. Molecular weights (kDa) of protein standards are marked on the right side. The two major bands of 120 kDa and 50 kDa and the minor smears of Kcnj10 reflect variable protein glycosylation, stoichiometry, and ubiquitination, as previously reported,9 and all are included in the quantitative analysis.
(B) Quantification of Kcnj10 expression normalized against β-tubulin control expression. Reduced expression of Kcnj10 in the stria vascularis of Slc26a4+/− and Slc26a4−/− mice as compared to WT mice (mean percentage ± SE, n = 3) is shown as scaled bars. The differences in Kcnj10 expression between Slc26a4+/− and Slc26a4+/+ mice and between Slc26a4−/− and Slc26a4+/+ mice are statistically significant (p < 0.05), as indicated by asterisks.
Abe,
Fluctuating sensorineural hearing loss associated with enlarged vestibular aqueduct maps to 7q31, the region containing the Pendred gene.
1999, Pubmed
Abe,
Fluctuating sensorineural hearing loss associated with enlarged vestibular aqueduct maps to 7q31, the region containing the Pendred gene.
1999,
Pubmed
Albert,
SLC26A4 gene is frequently involved in nonsyndromic hearing impairment with enlarged vestibular aqueduct in Caucasian populations.
2006,
Pubmed
Azaiez,
Genotype-phenotype correlations for SLC26A4-related deafness.
2007,
Pubmed
Bodmer,
Common and rare variants in multifactorial susceptibility to common diseases.
2008,
Pubmed
Choi,
Hypo-functional SLC26A4 variants associated with nonsyndromic hearing loss and enlargement of the vestibular aqueduct: genotype-phenotype correlation or coincidental polymorphisms?
2009,
Pubmed
,
Xenbase
Cohen,
Multiple rare alleles contribute to low plasma levels of HDL cholesterol.
2004,
Pubmed
Djukic,
Conditional knock-out of Kir4.1 leads to glial membrane depolarization, inhibition of potassium and glutamate uptake, and enhanced short-term synaptic potentiation.
2007,
Pubmed
Everett,
Targeted disruption of mouse Pds provides insight about the inner-ear defects encountered in Pendred syndrome.
2001,
Pubmed
Everett,
Pendred syndrome is caused by mutations in a putative sulphate transporter gene (PDS).
1997,
Pubmed
Everett,
Expression pattern of the mouse ortholog of the Pendred's syndrome gene (Pds) suggests a key role for pendrin in the inner ear.
1999,
Pubmed
Grimberg,
A simple and efficient non-organic procedure for the isolation of genomic DNA from blood.
1989,
Pubmed
Kryukov,
Most rare missense alleles are deleterious in humans: implications for complex disease and association studies.
2007,
Pubmed
Li,
A mutation in PDS causes non-syndromic recessive deafness.
1998,
Pubmed
Marcus,
KCNJ10 (Kir4.1) potassium channel knockout abolishes endocochlear potential.
2002,
Pubmed
Marcus,
Characterization of potassium permeability of cochlear duct by perilymphatic perfusion of barium.
1984,
Pubmed
Neusch,
Kir4.1 potassium channel subunit is crucial for oligodendrocyte development and in vivo myelination.
2001,
Pubmed
Park,
Genetic basis of hearing loss associated with enlarged vestibular aqueducts in Koreans.
2005,
Pubmed
Pera,
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.
2008,
Pubmed
Pera,
Functional assessment of allelic variants in the SLC26A4 gene involved in Pendred syndrome and nonsyndromic EVA.
2008,
Pubmed
Pessia,
Subunit positional effects revealed by novel heteromeric inwardly rectifying K+ channels.
1996,
Pubmed
,
Xenbase
Prasad,
Pendred syndrome and DFNB4-mutation screening of SLC26A4 by denaturing high-performance liquid chromatography and the identification of eleven novel mutations.
2004,
Pubmed
Pryor,
SLC26A4/PDS genotype-phenotype correlation in hearing loss with enlargement of the vestibular aqueduct (EVA): evidence that Pendred syndrome and non-syndromic EVA are distinct clinical and genetic entities.
2005,
Pubmed
Rotman-Pikielny,
Retention of pendrin in the endoplasmic reticulum is a major mechanism for Pendred syndrome.
2002,
Pubmed
Scholl,
Seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (SeSAME syndrome) caused by mutations in KCNJ10.
2009,
Pubmed
Singh,
Free radical stress-mediated loss of Kcnj10 protein expression in stria vascularis contributes to deafness in Pendred syndrome mouse model.
2008,
Pubmed
Stinckens,
Pendred syndrome redefined. Report of a new family with fluctuating and progressive hearing loss.
2002,
Pubmed
Takeuchi,
Intravascularly applied K(+)-channel blockers suppress differently the positive endocochlear potential maintained by vascular perfusion.
1996,
Pubmed
Takeuchi,
Dye-coupling of melanocytes with endothelial cells and pericytes in the cochlea of gerbils.
1998,
Pubmed
Tsukamoto,
Distribution and frequencies of PDS (SLC26A4) mutations in Pendred syndrome and nonsyndromic hearing loss associated with enlarged vestibular aqueduct: a unique spectrum of mutations in Japanese.
2003,
Pubmed
Wang,
A distinct spectrum of SLC26A4 mutations in patients with enlarged vestibular aqueduct in China.
2007,
Pubmed
Wang,
Mutational analysis of the tyrosine phosphatome in colorectal cancers.
2004,
Pubmed
Wangemann,
Loss of cochlear HCO3- secretion causes deafness via endolymphatic acidification and inhibition of Ca2+ reabsorption in a Pendred syndrome mouse model.
2007,
Pubmed
Wangemann,
Loss of KCNJ10 protein expression abolishes endocochlear potential and causes deafness in Pendred syndrome mouse model.
2004,
Pubmed
Yang,
Transcriptional control of SLC26A4 is involved in Pendred syndrome and nonsyndromic enlargement of vestibular aqueduct (DFNB4).
2007,
Pubmed
Yoshino,
The immunohistochemical analysis of pendrin in the mouse inner ear.
2004,
Pubmed
