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Genetic heterogeneity in patients with Bartter syndrome type 1.

ABSTRACT: Bartter syndrome (BS) type 1 is an autosomal recessive kidney disorder caused by loss?of?function mutations in the solute carrier family 12 member 1 (SLC12A1) gene. To date, 72 BS type 1 patients harboring SLC12A1 mutations have been documented. Of these 144 alleles studied, 68 different disease?causing mutations have been detected in 129 alleles, and no mutation was detected in the remaining 15 alleles. The mutation types included missense/nonsense mutations, splicing mutations and small insertions and deletions ranging from 1 to 4 nucleotides. A large deletion encompassing a whole exon in the SLC12A1 gene has not yet been reported. The current study initially identified an undocumented homozygous frameshift mutation (c.1833delT) by Sanger sequencing analysis of a single infant with BS type 1. However, in a subsequent analysis, the mutation was detected only in the father's DNA. Upon further investigation using a next?generation sequencing approach, a deletion in exons 14 and 15 in both the patient and patient's mother was detected. The deletion was subsequently confirmed by use of a long?range polymerase chain reaction and was determined to be 3.16 kb in size based on sequencing of the junction fragment. The results of the present study demonstrated that pathogenic variants of SLC12A1 are heterogeneous. Large deletions appear to serve an etiological role in BS type 1, and may be more prevalent than previously thought.

SUBMITTER: Sun M

PROVIDER: S-EPMC5364841 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Genetic heterogeneity in patients with Bartter syndrome type 1.

Sun Mingran M Ning Jing J Xu Weihong W Zhang Han H Zhao Kaishu K Li Wenfu W Li Guiying G Li Shibo S

Molecular medicine reports 20161221 2

Bartter syndrome (BS) type 1 is an autosomal recessive kidney disorder caused by loss‑of‑function mutations in the solute carrier family 12 member 1 (SLC12A1) gene. To date, 72 BS type 1 patients harboring SLC12A1 mutations have been documented. Of these 144 alleles studied, 68 different disease‑causing mutations have been detected in 129 alleles, and no mutation was detected in the remaining 15 alleles. The mutation types included missense/nonsense mutations, splicing mutations and small insert ...[more]

PMID: 28000888

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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.

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Genetic heterogeneity in patients with Bartter syndrome type 1.

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Genetic heterogeneity in patients with Bartter syndrome type 1.

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