Historical and geographical distribution of the founder mutation c.610G>A; p.Ala204Thr in the CLCNKB gene linked to Bartter syndrome type III in Spain.
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SUBMITTER: Peces R
PROVIDER: S-EPMC8323134 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ObjectiveType III Bartter syndrome (BS) is caused by loss-of-function mutations in the gene encoding basolateral chloride channel ClC-Kb (CLCNKB), and is characterized by hypokalemic metabolic alkalosis and hyperreninemic hyperaldosteronism. Here, we investigated the molecular defects in four Chinese children with clinical manifestations of Bartter syndrome.MethodsThe genomic DNA of the four patients was screened for gene variations using whole-exome sequencing (WES). The candidate variants were validated by direct Sanger sequencing. Quantitative PCR (qPCR) was subsequently performed to confirm the whole CLCNK gene deletion mutation. A minigene assay and reverse transcription PCR (RT-PCR) were performed to analyze the effect of splice variants in vitro.ResultsOur patients showed early onset age with hyponatremia, hypokalemia, hypochloremia, repeated vomiting and growth retardation, suggesting Bartter syndrome. Genetic analysis revealed that all patients carried compound heterozygous or homozygous truncating variants in the CLCNKB gene. In particular, we identified a novel nonsense variant c.239G > A (p.(Trp80*)), two splice site variants (c.1053-1 G > A and c.1228-2A > G), a whole gene deletion, and a novel synonymous variant c.228A > C (p.(Arg76Arg)) which located -2 bp from the 5' splice donor site in exon 3. Furthermore, our in vitro minigene analysis revealed c.228A > C, c.1053-1G > A, and c.1228-2A > G cause the skipping of exon 3, exon 12, and exon 13, respectively.ConclusionOur results support that the whole CLCNKB gene deletion is the most common mutation in Chinese patients with type III BS, and truncating and whole gene deletion variants may account for a more severe phenotype of patients. We verified the pathogenic effect of three splicing variants (c.228A > C, c.1053-1G > A, and c.1228-2A > G) which disturbed the normal mRNA splicing, suggesting that splice variants play an important role in the molecular basis of type III BS, and careful molecular profiling of these patients will be essential for future effective personalized treatment options.
| S-EPMC7047732 | biostudies-literature
Project description:BackgroundBartter's syndrome is a heterogeneous disorder characterized by deficient renal reabsorption of sodium and chloride, and hypokalemic metabolic alkalosis with hyper-reninemia and hyperaldosteronemia. Bartter syndrome type III (BS type III), due to mutations in the CLCNKB gene, is highly variable. The aim of our study was to describe the clinical presentation in a Chinese girl with BS type III and to explore mutations or SNPs of CLCNKB gene in her family.Case presentationThe clinic data of the patient was collected. Mutations or SNPs were investigated by sequencing of the exon of CLCNKB gene. The clinic analysis confirmed the diagnosis of BS type III. The coexistence of 13 reported SNPs and 11 novel SNPs of CLCNKB gene were found in the patient and her parent. a novel heterozygous C to G transition at nucleotide 2471 in exon 20 of CLCNKB gene harbored uniquely by the patient were revealed.ConclusionA novel heterozygous C to G mutation at nucleotide 2471 of CLCNKB gene and some new SNPs were identified in a Chinese girl with BS type III having persistent hypokalemia. The novel mutation and SNPs make the genetic background of the patient more complicated.
| S-EPMC3574998 | biostudies-literature
Project description:BackgroundBartter syndrome (BS) is a rare autosomal recessive disorder of salt reabsorption at the thick ascending limb of the Henle loop, characterized by hypokalemia, salt loss, metabolic alkalosis, hyperreninemic hyperaldosteronism with normal blood pressure. BS type III, often known as classic BS (CBS), is caused by loss-of-function mutations in CLCNKB (chloride voltage-gated channel Kb) encoding basolateral ClC-Kb.Case presentationWe reported a 15-year-old CBS patient with a compound heterozygous mutation of CLCNKB gene. She first presented with vomiting, hypokalemic metabolic alkalosis at the age of 4 months, and was clinically diagnosed as CBS. Indomethacin, spironolactone and oral potassium were started from then. During follow-up, the serum electrolyte levels were generally normal, but the patient showed failure to thrive and growth hormone (GH) deficiency was diagnosed. The recombinant human GH therapy was performed, and the growth velocity was improved. When she was 14, severe proteinuria and chronic kidney disease (CKD) were developed. Renal biopsy showed focal segmental glomerulosclerosis (FSGS) with juxtaglomerular apparatus cell hyperplasia, and genetic testing revealed a point deletion of c.1696delG (p. Glu566fs) and a fragment deletion of exon 2-3 deletions in CLCNKB gene. Apart from the CBS, ostium secundum atrial septal defect (ASD) was diagnosed by echocardiography.ConclusionsThis is the first report of this compound heterozygous of CLCNKB gene in BS Children. Our findings contribute to a growing list of CLCNKB mutations associated with CBS. Some recessive mutations can induce CBS in combination with other mutations.
| S-EPMC6693093 | biostudies-literature
Project description:BackgroundType III Bartter syndrome (BS) is an autosomal recessive disease caused by mutations in the CLCNKB (chloride voltage-gated channel Kb) gene that encodes CLC-Kb. CLC-Kb is mainly located in the thick ascending limb of Henle's loop and regulates chloride efflux from tubular epithelial cells to the interstitium. Type III BS is characterized by metabolic alkalosis, renal salt wasting, hyperreninemia, and hyperaldosteronism with normal blood pressure.Case presentationWe reported the case of a 3-day-old girl whose initial symptom we diagnosed as jaundice, but we accidentally found metabolic alkalosis. She showed recurrent metabolic alkalosis, hypokalemia, and hypochloremia and also had hyperreninemia and hyperaldosteronism with normal blood pressure. Both oral potassium supplements and potassium infusion therapy were unable to entirely restore the electrolyte imbalance. She was suspected of Bartter syndrome and genetic tests were performed on her and her parents. Next-generation sequencing identified CLCNKB gene mutation including heterozygous mutation c.1257delC (p.M421Cfs*58) and a low-level mutation c.595G > T (p.E199*); both mutations were also verified in the parents.ConclusionWe reported the case of a classic Bartter syndrome in a newborn with a heterozygous frameshift mutation and a mosaic non-sense mutation in the CLCNKB gene.
| S-EPMC10149701 | biostudies-literature
Project description:Bartter syndrome (BS) is an inherited renal tubular disorder characterized by low or normal blood pressure, hypokalemic metabolic alkalosis, and hyperreninemic hyperaldosteronism. Type III BS is caused by loss-of-function mutations in CLCNKB encoding basolateral ClC-Kb. The clinical phenotype of patients with CLCNKB mutations has been known to be highly variable, and cases that are difficult to categorize as type III BS or other hereditary tubulopathies, such as Gitelman syndrome, have been rarely reported. We report a case of a 10-year-old Korean boy with atypical clinical findings caused by a novel CLCNKB mutation. The boy showed intermittent muscle cramps with laboratory findings of hypokalemia, severe hypomagnesemia, and nephrocalcinosis. These findings were not fully compatible with those observed in cases of BS or Gitelman syndrome. The CLCNKB mutation analysis revealed a heterozygous c.139G>A transition in exon 13 [p.Gly(GGG)465Glu(GAG)]. This change is not a known mutation; however, the clinical findings and in silico prediction results indicated that it is the underlying cause of his presentation.
| S-EPMC5177689 | biostudies-literature
Project description:The p.Ala204Thr mutation (exon 7) of the CLCNKB gene is a "founder" mutation that causes most of type III Bartter syndrome cases in Spain. We performed genetic analysis of the CLCNKB gene, which encodes for the chloride channel protein ClC-Kb, in a cohort of 26 affected patients from 23 families. The diagnostic algorithm was: first, detection of the p.Ala204Thr mutation; second, detecting large deletions or duplications by Multiplex Ligation-dependent Probe Amplification and Quantitative Multiplex PCR of Short Fluorescent Fragments; and third, sequencing of the coding and flanking regions of the whole CLCNKB gene. In our genetic diagnosis, 20 families presented with the p.Ala204Thr mutation. Of those, 15 patients (15 families) were homozygous (57.7% of overall patients). Another 8 patients (5 families) were compound heterozygous for the founder mutation together with a second one. Thus, 3 patients (2 siblings) presented with the c. -19-?_2053+? del deletion (comprising the entire gene); one patient carried the p.Val170Met mutation (exon 6); and 4 patients (3 siblings) presented with the novel p.Glu442Gly mutation (exon 14). On the other hand, another two patients carried two novel mutations in compound heterozygosis: one presented the p.Ile398_Thr401del mutation (exon 12) associated with the c. -19-?_2053+? del deletion, and the other one carried the c.1756+1G>A splice-site mutation (exon 16) as well as the already described p.Ala210Val change (exon 7). One case turned out to be negative in our genetic screening. In addition, 51 relatives were found to be heterozygous carriers of the described CLCNKB mutations. In conclusion, different mutations cause type III Bartter syndrome in Spain. The high prevalence of the p.Ala204Thr in Spanish families thus justifies an initial screen for this mutation. However, should it not be detected further investigation of the CLCNKB gene is warranted in clinically diagnosed families.
| S-EPMC3776854 | biostudies-literature
Project description:An Iranian girl with clinical symptoms of Bartter syndrome like hypokalemia, polyuria, polydipsia, hyponatremia, and hypochloremic alkalosis was referred to us in whom the CLCNKB gene was genetically evaluated using Sanger sequencing. A homozygous pathogenic variant of c.1332_1335delCTCT was detected in this patient.
| S-EPMC9734084 | biostudies-literature
Project description:BackgroundType III Bartter syndrome (BS), often known as classic Bartter syndrome is caused by variants in CLCNKB gene, which encoding the basolateral chloride channel protein ClC-Kb, and is characterized by renal salt wasting, hypokalemia, metabolic alkalosis, increased renin, and aldosterone levels.MethodsA 2-year-old boy presented severe malnutrition, severe metabolic alkalosis and severe hypokalemia and was clinically diagnosed with BS. The trio exome sequencing (ES) was performed to discover the genetic cause of this patient, followed by validation using Sanger sequencing and quantitative polymerase chain reaction subsequently.ResultsThe genetic analysis indicated that this patient with a compound heterozygous variants of CLCNKB gene including a novel nonsense variant c.876 T > A and a whole-gene deletion. The two variants were inherited from his parents, respectively. Subsequently, target sequencing of CLCNKB gene was performed for next pregnancy, and prenatal genetic diagnosis was provided for the family.ConclusionsThe results of current study identified the compound heterozygous variants in a patient with classic BS. The novel variant expands the spectrum of CLCNKB variants in BS. Our study also indicates that ES is an alternative tool to simultaneously detect single-nucleotide variants and copy-number variants.
| S-EPMC9544217 | biostudies-literature
Project description:ObjectiveLarge kindreds segregating familial Alzheimer disease (FAD) offer the opportunity of studying clinical variability as observed for presenilin 1 (PSEN1) mutations. Two early-onset FAD (EOFAD) Calabrian families with PSEN1 Met146Leu (ATG/CTG) mutation constitute a unique population descending from a remote common ancestor. Recently, several other EOFAD families with the same mutation have been described worldwide.MethodsWe searched for a common founder of the PSEN1 Met146Leu mutation in families with different geographic origins by genealogic and molecular analyses. We also investigated the phenotypic variability at onset in a group of 50 patients (mean age at onset 40.0 +/- 4.8 years) by clinical, neuropsychological, and molecular methodologies.ResultsEOFAD Met146Leu families from around the world resulted to be related and constitute a single kindred originating from Southern Italy before the 17th century. Phenotypic variability at onset is broad: 4 different clinical presentations may be recognized, 2 classic for AD (memory deficits and spatial and temporal disorientation), whereas the others are expressions of frontal impairment. The apathetic and dysexecutive subgroups could be related to orbital-medial prefrontal cortex and dorsolateral prefrontal cortex dysfunction.ConclusionsGenealogic and molecular findings provided evidence that the PSEN1 Met146Leu families from around the world analyzed in this study are related and represent a single kindred originating from Southern Italy. The marked phenotypic variability might reflect early involvement by the pathologic process of different cortical areas. Although the clinical phenotype is quite variable, the neuropathologic and biochemical characteristics of the lesions account for neurodegenerative processes unmistakably of Alzheimer nature.
| S-EPMC3672006 | biostudies-literature
Project description:Patients with renal diseases associated with salt-losing tubulopathies categorized as Gitelman and classic form of Bartter syndrome have undergone genetic screening for possible mutation capture in two different genes: SLC12A3 and CLCNKB. Clinical symptoms of these two diseases may overlap. Bartter syndrome and Gitelman syndrome are autosomal recessive salt-losing tubulopathies with hypokalemia, metabolic alkalosis, hyperreninemia, hyperplasia of the juxtaglomerular apparatus, hyperaldosteronism, and, in some patients, hypomagnesemia. Here we describe four patients from an inbred family with a novel missense variant in the CLCNKB gene. All of patients are asymptomatic; yet they have the typical metabolic abnormality of salt losing tubulopathies. One of those patients had hypomagnesaemia while others not. Clinical and laboratory data of all patients was described. All 4 patients have a homozygous c.490G > T missense variant in exon 5 of the CLCNKB gene. This variant alters a glycine into a cysteine on amino acid position 164 of the resulting protein (p.Gly164Cys). The c.490G > T variant is a novel variant not previously described in other patients nor controls. Polyphen analysis predicts the variation to be possibly damaging. Analysis of SLC12A3 was normal. Here in we are describing a novel homozygous c.490G > T missense variation was identified in exon 5 of the CLCNKB gene was identified in an Emirati patients with a mild manifestation of Bartter - Gitelman syndrome.
| S-EPMC3977018 | biostudies-literature