Skip Navigation


NDT Advance Access originally published online on May 9, 2008
Nephrology Dialysis Transplantation 2008 23(10):3120-3125; doi:10.1093/ndt/gfn229
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
23/10/3120    most recent
gfn229v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Riveira-Munoz, E.
Right arrow Articles by Dahan, K.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Riveira-Munoz, E.
Right arrow Articles by Dahan, K.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


Evaluating PVALB as a candidate gene for SLC12A3-negative cases of Gitelman's syndrome

Eva Riveira-Munoz1, Olivier Devuyst1, Hendrica Belge1, Nikola Jeck2, Laurence Strompf3, Rosa Vargas-Poussou3,4, Xavier Jeunemaître3,4, Anne Blanchard3, Nine V. Knoers5, Martin Konrad6 and Karin Dahan7

1 Division of Nephrology, Université catholique de Louvain, Brussels, Belgium 2 Department of Pediatric Nephrology, University Children's Hospital, Marburg, Germany 3 AP-HP, Département de Génétique Moléculaire, Hôpital Européen George Pompidou 4 Université Paris-Descartes, Faculté de Médecine, Paris, France 5 Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands 6 Department of Pediatric Nephrology, University Children's Hospital, Münster, Germany 7 Center for Human Genetics, Université catholique de Louvain, Saint-Luc Academic Hospital, Brussels, Belgium

Olivier Devuyst, Université catholique de Louvain, 10 Avenue Hippocrate, Brussels B-1200, Belgium. Tel: +32-2-764-5450; Fax: +32-2-764-5455; E-mail: olivier.devuyst{at}uclouvain.be



   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background. Loss-of-function mutations in SLC12A3 coding for the thiazide-sensitive NaCl cotransporter (NCC) cause Gitelman's syndrome (GS), a recessively inherited salt-losing tubulopathy. Most GS patients are compound heterozygous. However, up to 30% of GS patients carry only a single mutant allele, and a normal SLC12A3 screening is also observed in a small subset of patients. Locus heterogeneity could explain the lack of detection of mutant SLC12A3 alleles in GS patients. The renal phenotype of the parvalbumin knockout mice pointed to PVALB as a candidate gene for GS for SLC12A3-negative cases.

Methods. PCR and direct sequencing of PVALB was performed in 132 GS patients in whom only one or no (N = 79) mutant SLC12A3 allele was found. The possible interference of biallelic SNPs (single nucleotide polymorphisms) on normal transcription or normal splicing was investigated. Genotyping of 110 anonymous blood donors was performed to determine the allelic frequency in the normal population.

Results. No sequence variants resulting in amino acid substitution or truncated protein within the PVALB gene were found in the 264 chromosomes tested. Ten biallelic SNPs, including six novel polymorphisms, were identified: five in the 5' UTR, none of them affecting predicted regulatory elements; three in the coding region, without alteration of the consensus splice sites, and two in the 3' UTR. The observed allelic frequencies did not differ significantly between GS patients and controls.

Conclusion. Our results strongly suggest that mutations in the PVALB gene are not involved in GS patients who harbour a single or no mutant SLC12A3 allele.

Keywords: distal convoluted tubule (DCT); NCC; parvalbumin; sodium-chloride cotransporter; thiazide



   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Discussion
 References
 
Gitelman's syndrome (GS; MIM 263800 [OMIM] ) is a salt-losing tubulopathy associated with hypokalaemic alkalosis, hypomagnesaemia and hypocalciuria. Loss-of-function mutations in the SLC12A3 gene that encodes the thiazide-sensitive Na+-Cl– cotransporter (NCC) were found to be responsible for the disease [1]. NCC is expressed in the cells lining the distal convoluted tubule (DCT) of the kidney, a segment responsible for the reabsorption of 5–10% of total filtered NaCl [2]. The incidence of GS may be as high as 1/1000 births in some populations [3], and it is characterized by a variable expression in terms of age at presentation, and nature and severity of the biochemical abnormalities and clinical manifestations. This significant phenotypic heterogeneity is observed not only between all patients harbouring SLC12A3 mutations but also among family members or patients with identical mutations [4,5].

Although GS is transmitted as an autosomal recessive trait, up to 30% of GS patients are found to carry only one mutant allele by classical SLC12A3 screening [6]. In addition, no mutations are detected in some patients presenting all clinical features of GS [7]. Genetic heterogeneity could be one explanation for this failure in the detection of SLC12A3 mutant alleles.

Our group has recently demonstrated that mice lacking parvalbumin (PV) harbour several manifestations similar to GS [8]. PV is a cytosolic protein that is encoded by the PVALB gene located on the long arm of chromosome 22 (22q13.1). In the mammalian kidney, PV is restricted to the DCT where it co-distributes with NCC [8,9]. Detailed phenotyping of Pvalb knockout (KO) mice indicated that the lack of PV is associated with a mild NaCl wasting, abnormal Ca2+ handling and stronger bones [10]. Furthermore, the lack of PV induced a significant decrease in the expression of NCC at the mRNA and protein level, suggesting a functional link between PV, intracellular Ca2+ signalling and NCC expression [8]. Since the expression of PV in the human kidney is also restricted to the initial part of DCT [8], we hypothesized that mutations in the PVALB gene could be involved in GS patients with unidentified SLC12A3 mutations and/or in those in whom only one mutant allele was detected.



   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Discussion
 References
 
Patients’ recruitment
The study group included 132 unrelated patients clinically diagnosed as having GS, originating from the St-Luc Academic Hospital (Brussels), the Hôpital Européen George Pompidou (Paris), the Radboud University Nijmegen Medical Centre (Nijmegen) and the University Children's Hospital (Marburg). All patients met the classical diagnostic criteria for GS including hypokalaemia due to renal potassium wasting associated with metabolic alkalosis, hypomagnesaemia, either hypo- or normocalciuria, normal (or low) blood pressure and normal renal function [11,12]. A similar SLC12A3 molecular testing by sequence analysis of the entire coding region (26 exons, with ~50 nucleotides in the 5' and 3' part of each exon) was routinely performed in each laboratory. The present screening did not include gene dosage, regulatory region sequencing or transcript analysis. There were no related individuals included in the analysis. Based on SLC12A3 genotyping, two groups were then distinguished: a group of 53 simple heterozygous patients, i.e. in which only one mutant SLC12A3 allele could be detected, and another group of 79 patients in which the screening for SLC12A3 mutations was strictly negative, i.e. in which no mutant allele was identified. DNAs from 110 healthy blood donors served as normal controls.

PVALB mutation analysis
Total DNA was extracted from peripheral blood leukocytes according the manufacturer's instructions (Gentra Systems, Puregene, Minneapolis, USA). Five primer pairs were designed using Primer 3 software (http://biotools. umassmed.edu/bioapps/primer3_www.cgi) to amplify by PCR the coding region and flanking intronic sequences of the human PVALB gene and part of its 5' and 3' UTR (Table 1). Thirty cycles of PCR were performed in the presence of 1.5 µl MgCl2 25 mM using AmpliTaq Gold (Perkin Elmer Applied Biosystems, Foster City, CA, USA). The PCR products were then directly sequenced with the Big Dye terminator kit (Perkin Elmer Applied Biosystems). Sequence reactions were purified with MultiScreen SEQ384 Filter Plate (Millipore, Billerica, MA, USA) and SephadexTM G-50 DNA Grade Fine (Amersham Biosciences, Piscataway, NJ, USA) dye terminator removal, before analysis on an ABI3100 capillary sequencer (Perkin Elmer Applied Biosystems). PVALB mutation analysis was performed in 46 patients by single-strand conformation analysis (SSCP) prior to direct sequencing, using the same primers as than those amplifying the coding sequences and the intron/exon boundaries. Aberrant bands, after separation on polyacrylamide gels, were directly sequenced on both strands.


View this table:
[in this window]
[in a new window]

  		Table 1 Human PVALB specific primers

 
Splice site prediction analyses were performed using Automated Splice Site Analyses (https://splice.cmh.edu) [13]. Predictions of putative promoter regions were evaluated using PROSCAN version 1.7 (http://bimas. dcrt.nih.gov/molbio/proscan/) [14] and Promoter 2.0 prediction server (http://www.cbs.dtu.dk/services/Promoter/) [15]. UCSC Genome Browser (http://genome.ucsc.edu/) was used to evaluate the presence of risk factors for genomic rearrangements through the RepeatMasker program.

Polymorphisms within the coding region are described at the cDNA level, based on the reference sequence NM_002854 [GenBank] , being nucleotide 1 being the first adenine of the translation initiation codon. Those polymorphisms located at the 5' or 3' UTR are described at the genomic level, based on the reference contig NT_011520 [GenBank] .11 between 16 586 000 and 16 606 532, minus strand.

Data analysis
Comparisons between groups were made by the {chi}2 test. The significance level was set at P < 0.05.



   Results
Top
 Abstract
 Introduction
 Patients and methods
 Results
Discussion
 References
 
One hundred and thirty-two individuals with a clinical and biochemical diagnosis of GS were screened for mutations in the entire coding region of the human PVALB gene and flanking intronic sequences, using PCR amplification and direct sequencing. Among these 132 individuals, there were 53 heterozygotes for a disease-causing mutation in SLC12A3 and 79 with a normal SLC12A3 sequence analysis. In the 264 chromosomes tested, analysis of PVALB failed to reveal sequences that could result in an amino acid substitution or in a truncated protein.

To assess the possible presence of mutations affecting regulatory regions in the 5' UTR, putative promoter region analyses were performed on a fragment expanding 5 kb located immediately upstream of the translation start site using two different promoter prediction servers. Both resources predicted a region of ~300 bp containing several segments highly likely active in the regulation of transcription. This region was situated at position –2800 before the first translation initiation codon and included a CAAT box (CCAAAAT) at position –2546 and a TATA box (TATATA) at position –2524 (Figure 1). Ten biallelic SNPs were detected in the human PVALB gene: five in the 5' UTR, three in the coding region and two in the 3' UTR region (Figure 1). The first sequence variation found in the 5' UTR region was a transition G to A located 2778 nucleotides before the translation initiation codon (g.191G > A). Two substitutions G to C were identified at position –2709 (g.260G > C) and –2634 (g.335G > C). One C to T transition was detected at position –2608 (g.361C > T). Finally, a substitution of G to A was identified at position –2562 (g.407G > A). Among them, the last four are included in the 300 bp region predicted to be highly likely active in the regulation of transcription. Within the coding region, the first nucleotide change was a G to A transition found in intron 3 (c.195-77G > A), whereas the last two were located at the end of intron 4, a T to C substitution (c.305-24T > C) and a C to T change (c.305-9G > T). In the 3' UTR region, two C to T substitutions were found, c.19147C > T and c.19202C > T, located 63 and 118 nucleotides downstream the TAA stop codon, respectively. A detailed search in the dbSNP database (http://www.ncbi.nlm.nih.gov, reviewed on September 2007) showed that among the 10 variants identified in our study, 6 were unknown (Table 2).


Figure 1
View larger version (13K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 1 Schematic PVALB and the identified polymorphisms. (A) Genomic context of PVALB on chromosome 22. A region expanding 50 kb on chromosome 22q13.1 is represented. Genes located on the vicinity of PVALB are shown in their corresponding orientation (arrows). NCF4, neutrophil cytosolic factor 4; FLJ90680, FLJ90680 protein; RABL4, RAB member of RAS oncogene family-like 4; CACNG2, calcium channel voltage-dependent gamma subunit 2. (B) PVALB gene structure comprising five exons (indicated by boxes, coding sequence in black). Dashed lines represent 5' and 3' UTR regions. Dotted box enclose the 300 bp putative promoter region including TATA and CAAT boxes. The location of the polymorphisms are indicated by asterisks, and their relative positions are shown.

 

View this table:
[in this window]
[in a new window]

  		Table 2 Variants detected in the human PVALB gene

 
We used Automated Splice Site analyses to assess whether the polymorphisms located in the flanking intronic sequences interfere with normal splicing of the pre-mRNA. None of them were considered to affect splicing, since the strength of the consensus splice sites did not undergo any change when the concerned nucleotide was replaced (data not shown). We observed that the two polymorphisms c.305-9G > T and g.19147C > T located upstream and downstream of the last exon and separated by 100 nucleotides are under perfect linkage disequilibrium, with a maximum expected r2 value equal to 1. Next, we genotyped the 10 SNPs covering the PVALB gene in 110 anonymous blood donors to determine the carrier frequency of each allele. The observed frequencies did not differ significantly between patients and controls (Table 2).



   Discussion
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
References
 
In this study, we tested the hypothesis that mutations in the PVALB gene could be involved in the pathogenesis of GS in those individuals in whom none or a single mutant SLC12A3 allele was identified.

Accumulated genetic data indicate that two SLC12A3 mutations inherited on both paternal and maternal alleles are found in the majority of the GS kindreds studied. However, a single heterozygous SLC12A3 mutation is detected in ~30% of GS patients [6,7,16]. In this group of individuals, the inheritance of GS could in principle be either recessive with an undetected second allele or digenic where SLC12A3 deleterious change would interact with a mutation in another gene. Potential explanations for the apparent lack of detection include the presence of mutations in regulatory fragments of SLC12A3 or in deeper intronic sequences which are not routinely screened, the involvement of unidentified large genomic rearrangements and the influence of epigenetic modifications and/or silent polymorphisms that could interfere in the function of the gene [16]. Locus heterogeneity could also be considered, especially in those GS individuals with normal SLC12A3 sequence analysis. Indeed, other genes may also be involved in the pathogenesis of GS, particularly if the proteins they encode participate in the complex handling of ions in the DCT. A case in point is CLCNKB, the gene that codes for the chloride channel ClC-Kb. Mutations in CLCNKB are responsible for classic Bartter's syndrome (cBS) that present during early childhood with failure to thrive, muscular weakness, marked hypochloraemic alkalosis and hypokalaemia [17]. Of interest, CLCNKB mutations have also been detected in three unrelated patients [18] and in patients from a large inbred Bedouin family [19] presenting overlapping clinical features between cBS and GS. However, the reduced subset of patients harbouring CLCNKB mutations suggests that this gene plays a limited role for the pathogenesis of GS.

The selection of PVALB as a candidate gene was based on its selective expression in the DCT of the human kidney and the recent observation that PVALB inactivation in mouse results in a discrete salt-losing phenotype, with a significant decrease in the expression of NCC in DCT cells secondary to alterations in intracellular Ca2+ signalling [8]. Furthermore, the PV KO mice showed increased tubular Ca2+ reabsorption and higher bone density, similar to features observed in Slc12a3 KO mice and GS patients [10–12].

To test whether mutations in the PVALB gene are involved in GS, 53 GS patients with a single identified mutation in SLC12A3 and 79 GS patients negative for the mutation screening were included in the study. The 132 individuals were screened for mutations in the entire coding region of the human PVALB gene and flanking intronic regions. No disease-associated sequence variations were identified in the 264 chromosomes tested. The screening revealed the presence of 10 SNPs (including 6 novel) covering the PVALB gene. Of them, three were found in intronic regions although none altered the strength of the consensus splice site when its possible interference with normal splicing of the pre-mRNA was tested, strongly suggesting that they are not disease-related variants.

After excluding the presence of disease-associated mutations in the coding region, we analysed the 5' UTR region using two servers (PROSCAN and Promoter 2.0) designed to find putative eukaryotic promoter sequences in primary sequence data in order to define a region containing elements highly likely active in the regulation of transcription for its further sequencing. A CAAT box and a TATA box were predicted within a putative promoter region of 300 bp. Both elements coincide with those predicted by Berchtold et al. who determined the genomic organization of the rat PV gene that showed 94% of similarity with the human counterpart [20,21]. Five of the 10 SNPs are located in the 5' UTR (4 of them into the predicted 300 bp region) but none of them affecting predicted regulatory elements, which very likely exclude their involvement in an abnormal transcription. The remaining two SNPs are located in the 3' UTR region. We then compared the frequency of each allele among the GS patient group and the control population. No statistically significant difference was observed, strongly suggesting that none of the 10 polymorphisms is related to the pathophysiology of GS. Although regulatory or deeper intronic sequences were not completely screened, we consider it rather unlikely that pathogenic mutations occur exclusively in these regions.

The use of single-exon mutational screening methods, like the one used in this study, could mask the presence of genomic rearrangements, including deletions or duplications. Risk factors for these events are the presence of short repetitive sequences serving as a substrate for recombination events between partially homologous sequences [22,23]. A detailed search for such sequences, mainly the interspersed elements, revealed that only intron 4, the longest intron of the gene with 12.7 kb, contains some short interspersed nuclear elements (SINEs) also named Alu sequences (23 elements) and four long interspersed nuclear elements (LINEs). However, in view of the high frequency (~50%) of c.305-9G > T polymorphism (Table 2), common genomic deletions encompassing the 3' UTR PVALB region can be considered as an unlikely event.

The rationale to test the potential role of PVALB in GS was based on the fact that PV regulates the expression of NCC in the mouse kidney. Our negative results, which suggest that PVALB is not involved in GS, could be explained by inter-species differences in the structure or function of the DCT. Reconstruction studies of the mouse nephron have shown special features in the length, transition and ultrastructure of segments including the DCT, which could have a physiologic importance [24]. Species differences in the response to thiazide diuretics have been observed [8]. In marked contrast to the GS in humans, the NCC-null mice showed no salt-losing phenotype and no disturbances in acid-base homeostasis [25]. Furthermore, the regulation of NCC in the DCT, in response to dietary NaCl content, angiotensin II or WNK1/4 kinases, could have distinct relevance in mouse and man [26,27]. In contrast with mouse, PV is not expressed in human muscles, explaining why the prolonged contraction–relaxation cycle of fast-twitch muscles observed in Pvalb KO mice [28] is not expected in humans lacking PV. However, PV is abundantly expressed in the GABA neurons in the mouse and human brain, and an increased susceptibility to epileptic seizures has been reported in Pvalb KO mouse [29]. Of note, seizures have been reported in a few GS patients [30]. It would thus be interesting to screen PVALB in patients with GS complicated by such central manifestations, which can be triggered by hypomagnesaemia.

In summary, our study addresses the genetic diagnosis of GS, probably the most frequent inherited tubulopathy. Based on a mouse model, we tested whether allelic variants in PVALB could be involved in GS patients who are simple heterozygous or negative for SLC12A3 mutations. Our negative results illustrate the limits of reverse genetics, in relation with inter-species differences in tubular functions and/or regulatory events. Further investigations will be necessary to evaluate the potential contribution of PVALB to the pathophysiology of human tubulopathies.



   Acknowledgments
 
We are grateful to the patients and their family members for their participation in the study. H. Debaix and X. Pepermans gave excellent technical assistance. These studies were supported in part by the Fonds National de la Recherche Scientifique, the Fonds de la Recherche Scientifique Médicale, an Action de Recherche Concertée (ARC 05/10-328), the IAP 6 (UCL), the EuReGene (FP6) and EUNEFRON (FP7) European projects, the INSERM and the French Ministry of Health (Centre de Référence Maladies Rénales Héréditaires Rares MARHEA).

Conflict of interest statement. None declared.



   References
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

  1. Simon DB, Nelson-Williams C, Bia MJ, et al. Gitelman's variant of Bartter's syndrome, inherited hypokalemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter. Nat Genet (1996) 12:24–30.[CrossRef][Web of Science][Medline]
  2. Obermuller N, Bernstein P, Velazquez H, et al. Expression of the thiazide-sensitive Na-Cl cotransporter in rat and human kidney. Am J Physiol (1995) 269:F900–F910.[Web of Science][Medline]
  3. Tago N, Kokubo Y, Inamoto N, et al. A high prevalence of Gitelman's syndrome mutations in Japanese. Hypertens Res (2004) 27:327–331.[CrossRef][Web of Science][Medline]
  4. Coto E, Rodriguez J, Jeck N, et al. A new mutation (intron 9 +1 G>T) in the SLC12A3 gene is linked to Gitelman syndrome in Gypsies. Kidney Int (2004) 65:25–29.[CrossRef][Web of Science][Medline]
  5. Lin SH, Cheng NL, Hsu YJ, et al. Intrafamilial phenotype variability in patients with Gitelman syndrome having the same mutations in their thiazide-sensitive sodium/chloride cotransporter. Am J Kidney Dis (2004) 43:304–312.[CrossRef][Web of Science][Medline]
  6. Lemmink HH, Knoers NV, Karolyi L, et al. Novel mutations in the thiazide-sensitive NaCl cotransporter gene in patients with Gitelman syndrome with predominant localization to the C-terminal domain. Kidney Int (1998) 54:720–730.[CrossRef][Web of Science][Medline]
  7. Riveira-Munoz E, Chang Q, Godefroid N, et al. Transcriptional and functional analyses of SLC12A3 mutations: new clues for the pathogenesis of Gitelman's syndrome. J Am Soc Nephrol (2007) 18:1271–1283.[Abstract/Free Full Text]
  8. Belge H, Gailly P, Schwaller B, et al. Renal expression of parvalbumin is critical for NaCl handling and response to diuretics. Proc Natl Acad Sci USA (2007) 104:14849–14854.[Abstract/Free Full Text]
  9. Loffing J, Loffing-Cueni D, Valderrabano V, et al. Distribution of transcellular calcium and sodium transport pathways along mouse distal nephron. Am J Physiol Renal Physiol (2001) 281:F1021–F1027.[Abstract/Free Full Text]
  10. Nicolet-Barousse L, Blanchard A, Roux C, et al. Inactivation of the Na-Cl co-transporter (NCC) gene is associated with high BMD through both renal and bone mechanisms: analysis of patients with Gitelman syndrome and Ncc null mice. J Bone Miner Res (2005) 20:799–808.[CrossRef][Web of Science][Medline]
  11. Peters M, Jeck N, Reinalter S. Clinical presentations of genotypically defined patients with hypokalemic salt-losing tubulopathies. Am J Med (2002) 112:183–191.[CrossRef][Web of Science][Medline]
  12. Warnock DG. Genetic forms of renal potassium and magnesium wasting. Am J Med (2002) 112:235–236.[CrossRef][Web of Science][Medline]
  13. Rogan N. Automated splicing mutation analysis by information theory. Human Mutat (2005) 25:334–342.[CrossRef][Web of Science][Medline]
  14. Prestridge DS. Predicting Pol II promoter sequences using transcription factor binding sites. J Mol Biol (1995) 249:923–932.[CrossRef][Web of Science][Medline]
  15. Knudsen S. Promoter 2.0: for the recognition of PolII promoter sequences. Bioinformatics (1999) 15:356–361.[Abstract/Free Full Text]
  16. Reissinger A, Ludwig M, Utsch B, et al. Novel NCCT gene mutations as a cause of Gitelman's syndrome and a systematic review of mutant and polymorphic NCCT alleles. Kidney Blood Press Res (2002) 25:354–362.[CrossRef][Web of Science][Medline]
  17. Konrad M, Vollmer M, Lemmink HH, et al. Mutations in the chloride channel gene CLCNKB as a cause of classic Bartter syndrome. J Am Soc Nephrol (2000) 11:1449–1459.[Abstract/Free Full Text]
  18. Jeck N, Konrad M, Peters M, et al. Mutations in the chloride channel gene, CLCNKB, leading to a mixed Bartter-Gitelman phenotype. Pediatr Res (2000) 48:754–758.[Web of Science][Medline]
  19. Zelikovic I, Szargel R, Hawash A, et al. A novel mutation in the chloride channel gene CLCNKB as a cause of Gitelman and Bartter syndromes. Kidney Int (2003) 63:24–32.[CrossRef][Web of Science][Medline]
  20. Berchtold MW, Epstein P, Beaudet AL, et al. Structural organization and chromosomal assignment of the parvalbumin gene. J Biol Chem (1987) 262:8696–8701.[Abstract/Free Full Text]
  21. Berchtold MW. Parvalbumin genes from human and rat are identical in intron/exon organization and contain highly homologous regulatory elements and coding sequences. J Mol Biol (1989) 210:417–427.[CrossRef][Web of Science][Medline]
  22. Abeysinghe SS, Chuzhanova N, Krawczak M, et al. Translocation and gross deletion breakpoints in human inherited disease and cancer I: nucleotide composition and recombination-associated motifs. Hum Mutat (2003) 22:229–244.[CrossRef][Web of Science][Medline]
  23. Chuzhanova N, Abeysinghe SS, Krawczak M, et al. Translocation and gross deletion breakpoints in human inherited disease and cancer II: potential involvement of repetitive sequence elements in secondary structure formation between DNA ends. Hum Mutat (2003) 22:245–251.[CrossRef][Web of Science][Medline]
  24. Zhai XY, Thomsen JS, Birn H, et al. Three-dimensional reconstruction of the mouse nephron. J Am Soc Nephrol (2006) 17:77–88.[Abstract/Free Full Text]
  25. Schultheis PJ, Lorenz JN, Meneton P, et al. Phenotype resembling Gitelman's syndrome in mice lacking the apical Na+-Cl– cotransporter of the distal convoluted tubule. J Biol Chem (1998) 273:29150–29155.[Abstract/Free Full Text]
  26. Yang CL, Angell J, Mitchell R, et al. WNK kinases regulate thiazide-sensitive Na-Cl cotransport. J Clin Invest (2003) 111:1039–1045.[CrossRef][Web of Science][Medline]
  27. Sandberg MB, Maunsbach AB, McDonough AA. Redistribution of distal tubule Na+-Cl– cotransporter (NCC) in response to a high-salt diet. Am J Physiol Renal Physiol (2006) 291:F503–F508.[Abstract/Free Full Text]
  28. Schwaller B, Dick J, Dhoot G, et al. Prolonged contraction-relaxation cycle of fast-twitch muscles in parvalbumin knockout mice. Am J Physiol (1999) 276:C395–C403.[Web of Science][Medline]
  29. Schwaller B, Tetko IV, Tandon P, et al. Parvalbumin deficiency affects network properties resulting in increased susceptibility to epileptic seizures. Mol Cell Neurosci (2004) 25:650–663.[CrossRef][Web of Science][Medline]
  30. Cruz DN, Shaer AJ, Bia MJ, et al, (Yale Gitelman's and Bartter's Syndrome Collaborative Study Group). Gitelman's syndrome revisited: an evaluation of symptoms and health-related quality of life. Kidney Int (2001) 59:710–717.[CrossRef][Web of Science][Medline]
Received for publication: 27.12.07
Accepted in revised form: 2. 4.08


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?



This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
23/10/3120    most recent
gfn229v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Riveira-Munoz, E.
Right arrow Articles by Dahan, K.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Riveira-Munoz, E.
Right arrow Articles by Dahan, K.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?