A Deep Intronic Mutation in the SLC12A3 Gene Leads to Gitelman Syndrome

Nozu, Kandai; Iijima, Kazumoto; Nozu, Yoshimi; Ikegami, Ei; Imai, Takehide; Fu, Xue Jun; Kono, Hiroshi; Nakanishi, Koichi; Yoshikawa, Norishige; Matsuo, Masafumi

doi:10.1203/pdr.0b013e3181b9b4d3

Cited by 37 publications

(21 citation statements)

References 17 publications

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“…Halpotype analysis with markers flanking the SLC12A3 demonstrated that c.1670 -191C3 T and c.2548ϩ253C3 T mutations are located on mutational hot spots rather than founder effect. Of interest, this c.1670 -191C3 T was only identified in Taiwan aborigines and identical to one reported from Japan and inherited from a Filipino maternal allele (35). Taiwan has been suggested to be the homeland of the Austronesian language family (36,37).…”

Section: Discussionsupporting

confidence: 75%

“…A recent study reported that GS patients with truncated mutations or splicing variants in at least one allele tended to manifest more severe symptoms (16). We found that the reported female patient from Japan and our female patients carrying deep intronic mutation appeared to exhibit moderate to severe symptoms (35). Whether the phenotypes in GS are modified by the deep intronic mutations merits further investigation.…”

Section: Discussionmentioning

confidence: 47%

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Recurrent Deep Intronic Mutations in the SLC12A3 Gene Responsible for Gitelman's Syndrome

Nozu

Iijima

et al. 2011

Clinical Journal of the American Society of Nephrology

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SummaryBackground and objectives Gitelman's syndrome (GS) is an autosomal recessive renal tubular disorder caused by mutations in the SLC12A3 gene encoding the thiazide-sensitive Na ϩ -Cl Ϫ cotransporter (NCC). Despite meticulous sequencing of genomic DNA, approximately one-third of GS patients are negative or heterozygotes for the known mutations.Design, Setting, Participants, & Measurements Because blood leukocytes express NCC mRNA, we evaluate whether deep intronic mutations contribute to GS patients with uniallelic or undetectable SLC12A3 mutations. Twenty-nine patients with GS (men/women ϭ 16/13), including eight negative and 21 uniallelic SLC12A3 mutations from 19 unrelated families, and normal controls were enrolled in an academic medical center. Analysis of cDNA from blood leukocytes, sequencing of the corresponding introns of genomic DNA for abnormal transcript, and analysis of NCC protein expression from renal biopsy were performed. Results We identified nine Taiwan aboriginal patients carrying c.1670 -191C3 T mutations in intron 13and 10 nonaboriginal patients carrying c.2548ϩ253C3 T mutations in intron 21 from 14 families (14/ 19). These two mutations undetected in 100 healthy subjects created pseudoexons containing new premature termination codons. Haplotype analysis with markers flanking SLC12A3 revealed that both mutations did not have founder effects. Apical NCC expression in the DCT of renal tissue was markedly diminished in two patients carrying deep intronic mutations.Conclusions Deep intronic mutations in SLC12A3 causing defective NCC expression can be identified with the RNA-based approach in patients with GS. c.1670 -191C3 T and c.2548ϩ253C3 T are hot spot mutations that can be screened in GS patients with uniallelic or negative SLC12A3 mutations.

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Section: Discussionsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 47%

Recurrent Deep Intronic Mutations in the SLC12A3 Gene Responsible for Gitelman's Syndrome

Nozu

Iijima

et al. 2011

Clinical Journal of the American Society of Nephrology

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“…However, these studies did not fully consider the effect of splice site mutations on COL4A5 expression. This study requires careful analysis of COL4A5 transcripts and assessment of intronic mutations, which have been increasingly identified as a cause of aberrant splicing for various disorders, including Alport syndrome (10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

X-Linked Alport Syndrome Caused by Splicing Mutations in COL4A5

Nozu

Vořechovský

Kono

et al. 2014

Clinical Journal of the American Society of Nephrology

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Background and objectives X-linked Alport syndrome is caused by mutations in the COL4A5 gene. Although many COL4A5 mutations have been detected, the mutation detection rate has been unsatisfactory. Some men with X-linked Alport syndrome show a relatively mild phenotype, but molecular basis investigations have rarely been conducted to clarify the underlying mechanism.Design, setting, participants, & measurements In total, 152 patients with X-linked Alport syndrome who were suspected of having Alport syndrome through clinical and pathologic investigations and referred to the hospital for mutational analysis between January of 2006 and January of 2013 were genetically diagnosed. Among those patients, 22 patients had suspected splice site mutations. Transcripts are routinely examined when suspected splice site mutations for abnormal transcripts are detected; 11 of them showed expected exon skipping, but others showed aberrant splicing patterns. The mutation detection strategy had two steps: (1) genomic DNA analysis using PCR and direct sequencing and (2) mRNA analysis using RT-PCR to detect RNA processing abnormalities.Results Six splicing consensus site mutations resulting in aberrant splicing patterns, one exonic mutation leading to exon skipping, and four deep intronic mutations producing cryptic splice site activation were identified. Interestingly, one case produced a cryptic splice site with a single nucleotide substitution in the deep intron that led to intronic exonization containing a stop codon; however, the patient showed a clearly milder phenotype for X-linked Alport syndrome in men with a truncating mutation. mRNA extracted from the kidney showed both normal and abnormal transcripts, with the normal transcript resulting in the milder phenotype. This novel mechanism leads to mild clinical characteristics.Conclusions This report highlights the importance of analyzing transcripts to enhance the mutation detection rate and provides insight into genotype-phenotype correlations. This approach can clarify the cause of atypically mild phenotypes in X-linked Alport syndrome.

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“…Recessive mutations were published in the SLC12A3 gene which encodes the Na-Cl cotransporter NCC(82). In up to 40% of patients the second mutation cannot be detected possibly due to deep intronic location or large genomic rearrangements(83–85). A Ncc knockout mouse model confirmed the human GS phenotype with hypomagnesemia and hypocalciuria but lacked volume contraction and metabolic alkalosis(86, 87).…”

Section: Gitelman-like Hypomagnesemiasmentioning

confidence: 99%

Inherited and acquired disorders of magnesium homeostasis

Wolf

2017

Current Opinion in Pediatrics

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Purpose of review Magnesium (Mg2+) imbalances are frequently overlooked. Hypermagnesemia usually occurs in preeclamptic women after Mg2+ therapy or in end-stage renal disease patients, while hypomagnesemia is more common with a prevalence of up to 15% in the general population. Increasing evidence points towards a role for mild to moderate, chronic hypomagnesemia in the pathogenesis of hypertension, type 2 diabetes mellitus, and metabolic syndrome. Recent findings The kidneys are the major regulator of total body Mg2+ homeostasis. Over the last decade the identification of the responsible genes in rare genetic disorders has enhanced our understanding of how the kidney handles Mg2+. The different genetic disorders and medications contributing to abnormal Mg2+ homeostasis are reviewed. Summary As dysfunctional Mg2+ homeostasis contributes to the development of many common human disorders, serum Mg2+ deserves closer monitoring. Hypomagnesemic patients may be asymptomatic or may have mild symptoms. In severe hypomagnesemia patients may present with neurological symptoms such as seizures, spasms or cramps. Renal symptoms include nephrocalcinosis and impaired renal function. Most conditions affect tubular Mg2+ reabsorption by disturbing the lumen-positive potential in the thick ascending limb or the negative membrane potential in the distal convoluted tubule.

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A Deep Intronic Mutation in the SLC12A3 Gene Leads to Gitelman Syndrome

Cited by 37 publications

References 17 publications

Recurrent Deep Intronic Mutations in the SLC12A3 Gene Responsible for Gitelman's Syndrome

Recurrent Deep Intronic Mutations in the SLC12A3 Gene Responsible for Gitelman's Syndrome

X-Linked Alport Syndrome Caused by Splicing Mutations in COL4A5

Inherited and acquired disorders of magnesium homeostasis

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