Simultaneous Mutations in the CLCNKB and SLC12A3 Genes in Two Siblings with Phenotypic Heterogeneity in Classic Bartter Syndrome

Department of Pediatrics, San Leopoldo Mandic Hospital, Merate, and Department of Pediatrics and Neonatology, University of Milan, Italy.
Pediatric Research (Impact Factor: 2.31). 01/2006; 58(6):1269-73. DOI: 10.1203/01.pdr.0000185267.95466.41
Source: PubMed


Two siblings (brother and sister) with renal tubular hypokalemic alkalosis underwent clinical, biochemical and molecular investigations. Although the biochemical findings were similar (including hypokalemia, metabolic alkalosis, hyperreninemia, hyperaldosteronism and normal blood pressure), the clinical findings were different: the boy, who also presented syndromic signs, developed glomerular proteinuria and renal biopsy revealed focal segmental glomerular sclerosis; the girl showed the typical signs of classic Bartter syndrome. As described in a previous paper, a heterozygous mutation (frameshift 2534delT) was demonstrated in the gene encoding the thiazide-sensitive NaCl co-transporter (SLC12A3) of the distal convoluted tubule; the second molecular analysis revealed a compound heterozygous mutation (A61D/V149E) in the CLCNKB chloride channel gene in both subjects, inherited in trans from the parents. The children were finally diagnosed as having classic Bartter syndrome. These cases represent the first report of the simultaneous presence of heterozygous and compound heterozygous mutations in the SLC12A3 and CLCNKB genes, both of which are involved in renal salt losing tubulopathies, and confirm previous observations regarding classic Bartter syndrome phenotype variability in the same kindred.

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    • "FSGS is a broadly defined pattern of injury, whereas genetic defects are revealed in clinical studies. It has been shown that mutations in Nephrin, ClC-K and NKCC2 are related to this disease [42], [43], [44]. "
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    ABSTRACT: GOLPH2 is a highly conserved protein. It is upregulated in a number of tumors and is being considered as an emerging biomarker for related diseases. However, the function of GOLPH2 remains unknown. The Xenopus model is used to study the function of human proteins. We describe the isolation and characterization of Xenopus golph2, which dimerizes and localizes to the Golgi in a manner similar to human GOLPH2. Xenopus golph2 is expressed in the pronephros during early development. The morpholino-mediated knockdown of golph2 results in edema formation. Additionally, Nephrin expression is enhanced in the glomus, and the expression of pronephric marker genes, such as atp1b1, ClC-K, NKCC2, and NBC1, is diminished in the tubules and duct. Expression patterns of the transcription factors WT1, Pax2, Pax8, Lim1, GATA3, and HNF1β are also examined in the golph2 knockdown embryos, the expression of WT1 is increased in the glomus and expanded laterally in the pronephric region. We conclude that the deletion of golph2 causes an increase in the expression of WT1, which may promote glomus formation and inhibit pronephric tubule differentiation.
    PLoS ONE 06/2012; 7(6):e38939. DOI:10.1371/journal.pone.0038939 · 3.23 Impact Factor
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    • "An unaffected sibling did not share this specific LCSH or recombinant thereof, supporting the possibility of a recessive sequence mutation in one of these genes in the proband. Sequence analysis of CLC- NKB revealed a homozygous missense variant (c.446T>A; p.V149E) that has previously been described as pathogenic [Bettinelli et al., 2005]. "
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    ABSTRACT: Microarray analysis has provided significant advances in the diagnosis of conditions resulting from submicroscopic chromosome abnormalities. It has been recommended that array testing should be a "first tier" test in the evaluation of individuals with intellectual disability, developmental delay, congenital anomalies, and autism. The availability of arrays with increasingly high probe coverage and resolution has increased the detection of decreasingly small copy number changes (CNCs) down to the intragenic or even exon level. Importantly, arrays that genotype SNPs also detect extended regions of homozygosity. We describe 14 examples of single gene disorders caused by intragenic changes from a consecutive set of 6,500 tests using high-resolution SNP microarrays. These cases illustrate the increased scope of cytogenetic testing beyond dominant chromosome rearrangements that typically contain many genes. Nine of the cases confirmed the clinical diagnosis, that is, followed a "phenotype to genotype" approach. Five were diagnosed by the laboratory analysis in the absence of a specific clinical diagnosis, that is, followed a "genotype to phenotype" approach. Two were clinically significant, incidental findings. The importance of astute clinical assessment and laboratory-clinician consultation is emphasized to optimize the value of microarrays in the diagnosis of disorders caused by single gene copy number and sequence mutations.
    Human Mutation 12/2011; 32(12):1500-6. DOI:10.1002/humu.21581 · 5.14 Impact Factor
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    • "Bartter syndrome (BS) is a rare inherited renal tubular disorder characterized by renal salt wasting, hypokalemic metabolic alkalosis and normotensive hyperreninemic hyperaldosteronism1, 2). Although BS is a typical tubular disorder, there have been several case reports of patients who developed focal segmental glomerulosclerosis (FSGS), a glomerular lesion, during the course of BS3-7). Such cases support a possible link between the two diseases, and indicate that stimulation of the renin-angiotensin system (RAS) and increased angiotensin II in response to chronic glomerular hyperfiltration due to salt-losing tubulopathy may lead to secondary FSGS3, 4, 8). "
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    ABSTRACT: Bartter syndrome (BS) is a clinically and genetically heterogeneous inherited renal tube disorder characterized by renal salt wasting, hypokalemic metabolic alkalosis and normotensive hyperreninemic hyperaldosteronism. There have been several case reports of BS complicated by focal segmental glomerulosclerosis (FSGS). Here, we have reported the case of a BS patient who developed FSGS and subsequent end-stage renal disease (ESRD) and provided a brief literature review. The patient presented with classic BS at 3 months of age and developed proteinuria at 7 years. Renal biopsy performed at 11 years of age revealed a FSGS perihilar variant. Hemodialysis was initiated at 11 years of age, and kidney transplantation was performed at 16 years of age. The post-transplantation course has been uneventful for more than 3 years with complete disappearance of BS without the recurrence of FSGS. Genetic study revealed a homozygous p.Trp(TGG)610Stop(TGA) mutation in the CLCNKB gene. In summary, BS may be complicated by secondary FSGS due to the adaptive response to chronic salt-losing nephropathy, and FSGS may progress to ESRD in some patients. Renal transplantation in patients with BS and ESRD results in complete remission of BS.
    Korean Journal of Pediatrics 01/2011; 54(1):36-9. DOI:10.3345/kjp.2011.54.1.36
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