NDT Advance Access originally published online on May 9, 2008
Nephrology Dialysis Transplantation 2008 23(10):3120-3125; doi:10.1093/ndt/gfn229
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Evaluating PVALB as a candidate gene for SLC12A3-negative cases of Gitelman's syndrome
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
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Abstract |
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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
Received for publication: 27.12.07
Accepted in revised form: 2. 4.08