Salt Wasting and Deafness Resulting from Mutations in Two Chloride Channels

Schlingmann, Karl Peter; Konrad, Martin; Jeck, Nikola; Waldegger, Petra; Reinalter, Stephan C.; Holder, Martin; Seyberth, Hannsjörg W.; Waldegger, Siegfried

doi:10.1056/nejmoa032843

Cited by 249 publications

(173 citation statements)

References 19 publications

Supporting

Mentioning

158

Contrasting

Unclassified

Order By: Relevance

“…Together, the genetic data suggest that impairment of the proteasome assembly and/or function caused by mutations in various proteasome components can lead to clinical disease. Other examples of digenic inheritance include conditions caused by double-heterozygous variants of structural proteins that are critical for organ function, including retinitis pigmentosa (30), the digenic inheritance of nonsyndromic deafness (31), Usher's syndrome (32), Bartter syndrome (33), and Hirschsprung's disease (34), and triallelic inheritance was found in patients with Bardet-Biedl syndrome (BBS) (35) and in isolated hypogonadotropic hypogonadism (36). In 2 recently described digenic conditions, the second gene acts as epigenetic or epistatic modifier, as observed in facioscapulohumeral muscular dystrophy (FSHD) (37) and in ataxia, dementia, and hypogonadotropism (38), respectively.…”

Section: Recapitulation Of Additive Effect Of Proteasome Defects On Pmentioning

confidence: 99%

Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type I IFN production

Brehm¹,

Liu²,

Sheikh³

et al. 2015

Journal of Clinical Investigation

281

244

View full text Add to dashboard Cite

Section: Recapitulation Of Additive Effect Of Proteasome Defects On Pmentioning

confidence: 99%

Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type I IFN production

Brehm¹,

Liu²,

Sheikh³

et al. 2015

Journal of Clinical Investigation

281

244

View full text Add to dashboard Cite

“…Furthermore, if the proposed concepts linking CLCNKA to heart failure are correct, it is likely that other gene variants with similar effects on the cardio-renal axis can also modify heart failure risk. We consider that the possibilities for such risk variants include rare or private nonsynonymous loss-of-function variants in CLCNKA (26,38), variants of the related CLCNKB gene that confer similar channel dysfunction, or variants of other genes that affect renal salt handling and therefore the renin-angiotensin set point. Thus, on the basis of the current genetic and functional data, we postulate that multiple genetic events inducing a common cardio-renal physiological response can modify heart failure risk.…”

Section: Discussionmentioning

confidence: 99%

Loss-of-function DNA sequence variant in the CLCNKA chloride channel implicates the cardio-renal axis in interindividual heart failure risk variation

Cappola

Matkovich

Wang

et al. 2011

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

View full text Add to dashboard Cite

Common heart failure has a strong undefined heritable component. Two recent independent cardiovascular SNP array studies identified a common SNP at 1p36 in intron 2 of the HSPB7 gene as being associated with heart failure. HSPB7 resequencing identified other risk alleles but no functional gene variants. Here, we further show no effect of the HSPB7 SNP on cardiac HSPB7 mRNA levels or splicing, suggesting that the SNP marks the position of a functional variant in another gene. Accordingly, we used massively parallel platforms to resequence all coding exons of the adjacent CLCNKA gene, which encodes the K a renal chloride channel (ClC-K a ). Of 51 exonic CLCNKA variants identified, one SNP (rs10927887, encoding Arg83Gly) was common, in linkage disequilibrium with the heart failure risk SNP in HSPB7, and associated with heart failure in two independent Caucasian referral populations (n = 2,606 and 1,168; combined P = 2.25 × 10 −6). Individual genotyping of rs10927887 in the two study populations and a third independent heart failure cohort (combined n = 5,489) revealed an additive allele effect on heart failure risk that is independent of age, sex, and prior hypertension (odds ratio = 1.27 per allele copy; P = 8.3 × 10 −7). Functional characterization of recombinant wild-type Arg83 and variant Gly83 ClC-K a chloride channel currents revealed ≈50% loss-of-function of the variant channel. These findings identify a common, functionally significant genetic risk factor for Caucasian heart failure. The variant CLCNKA risk allele, telegraphed by linked variants in the adjacent HSPB7 gene, uncovers a previously overlooked genetic mechanism affecting the cardiorenal axis.cardiomyopathy | genetic association

show abstract

“…This compensatory relationship was proposed because normal hearing is preserved with the loss-of-function of either variant, as demonstrated in ClC-K1 knockout mouse and Bartter_s syndrome type III (Simon et al 1997;Matsumura et al 1998). On the other hand, the loss of both ClC-Ks or their common b-subunit results in deafness (Estevez et al 2001;Schlingmann et al 2004). Message for ClC-K1 and -K2 was present in regions of freshly isolated spiral ligament tissues that were seeded for the primary cultures.…”

Section: Discussionmentioning

confidence: 99%

Identification of ClC-2 and CIC-K2 Chloride Channels in Cultured Rat Type IV Spiral Ligament Fibrocytes

Liang

Smythe

et al. 2007

JARO

View full text Add to dashboard Cite

Voltage-gated chloride channels (ClCs) are important mediators of cellular ion homeostasis and volume regulation. In an earlier study, we used immunohistochemical, Western blot, and reverse transcriptase PCR (RT-PCR) approaches to identify ClC-K variants in types II, IV, and V fibrocytes of the rodent spiral ligament. We have now confirmed the expression of ClC-K2 in these cells by in situ hybridization. All three of these fibrocyte subtypes are thought to be involved in cochlear K + recycling; thus, it is important to understand the precise mechanisms regulating their membrane conductance and the role played by ClCs in this process. In this study, we report the characterization of a secondary cell line derived from explants from the region of the rat spiral ligament underlying and inferior to the spiral prominence. The cultured cells were immunopositive for vimentin, Na,K/ATPase, Na,K,Cl-cotransporter, carbonic anhydrase isozyme II, and creatine kinase isozyme BB, but not for cytokeratins or Ca/ATPase, an immunostaining profile indicative of the type IV subtype. Evaluation of the cultures by RT-PCR and Western blot analysis confirmed the presence of both ClC-2 and -K2. Whole-cell patch clamp recordings identified two biophysically distinct Cl _ currents in the cultured cells. One, an inwardly rectifying Cl _ current activated by hyperpolarization or decreasing extracellular pH corresponded with the properties of ClC-2. The other, a weak outwardly rectifying Cl _ current regulated by extracellular pH, Cl _ , and Ca 2+ resembled the channel characteristics of ClC-K2 when expressed in Xenopus oocytes. These findings suggest that at least two functionally different chloride channels are involved in regulating membrane anion conductance in cultured type IV spiral ligament fibrocytes.

show abstract

Salt Wasting and Deafness Resulting from Mutations in Two Chloride Channels

Cited by 249 publications

References 19 publications

Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type I IFN production

Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type I IFN production

Loss-of-function DNA sequence variant in the CLCNKA chloride channel implicates the cardio-renal axis in interindividual heart failure risk variation

Identification of ClC-2 and CIC-K2 Chloride Channels in Cultured Rat Type IV Spiral Ligament Fibrocytes

Contact Info

Product

Resources

About