Cryptic exon activation in SLC12A3 in Gitelman syndrome

Kandai Nozu, Yoshimi Nozu, Keita Nakanishi, Takao Konomoto, Tomoko Horinouchi, Akemi Shono, Naoya Morisada, Shogo Minamikawa, Tomohiko Yamamura, Junya Fujimura, Koichi Nakanishi, Takeshi Ninchoji, Hiroshi Kaito, Ichiro Morioka, Mariko Ikeda, Igor Vorechovsky, Kazumoto Iijima

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Gitelman syndrome (GS) is an autosomal recessive renal tubulopathy characterized by hypokalemic metabolic alkalosis with hypocalciuria and hypomagnesemia. GS clinical symptoms range from mild weakness to muscular cramps, paralysis or even sudden death as a result of cardiac arrhythmia. GS is caused by loss-of-function mutations in the solute carrier family 12 member 3 (SLC12A3) gene, but molecular mechanisms underlying such a wide range of symptoms are poorly understood. Here we report cryptic exon activation in SLC12A3 intron 12 in a clinically asymptomatic GS, resulting from an intronic mutation c.1669+297 T>G that created a new acceptor splice site. The cryptic exon was sandwiched between the L3 transposon upstream and a mammalian interspersed repeat downstream, possibly contributing to inclusion of the cryptic exon in mature transcripts. The mutation was identified by targeted next-generation sequencing of candidate genes in GS patients with missing pathogenic SLC12A3 alleles. Taken together, this work illustrates the power of next-generation sequencing to identify causal mutations in intronic regions in asymptomatic individuals at risk of developing potentially fatal disease complications, improving clinical management of these cases.

Original languageEnglish
Pages (from-to)335-337
Number of pages3
JournalJournal of Human Genetics
Volume62
Issue number2
DOIs
Publication statusPublished - 01-02-2017

Fingerprint

Gitelman Syndrome
Exons
Mutation
Member 3 Solute Carrier Family 12
Muscle Cramp
Alkalosis
RNA Splice Sites
Case Management
Sudden Death
Paralysis
Introns
Genes
Cardiac Arrhythmias
Alleles
Kidney

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Nozu, K., Nozu, Y., Nakanishi, K., Konomoto, T., Horinouchi, T., Shono, A., ... Iijima, K. (2017). Cryptic exon activation in SLC12A3 in Gitelman syndrome. Journal of Human Genetics, 62(2), 335-337. https://doi.org/10.1038/jhg.2016.129
Nozu, Kandai ; Nozu, Yoshimi ; Nakanishi, Keita ; Konomoto, Takao ; Horinouchi, Tomoko ; Shono, Akemi ; Morisada, Naoya ; Minamikawa, Shogo ; Yamamura, Tomohiko ; Fujimura, Junya ; Nakanishi, Koichi ; Ninchoji, Takeshi ; Kaito, Hiroshi ; Morioka, Ichiro ; Ikeda, Mariko ; Vorechovsky, Igor ; Iijima, Kazumoto. / Cryptic exon activation in SLC12A3 in Gitelman syndrome. In: Journal of Human Genetics. 2017 ; Vol. 62, No. 2. pp. 335-337.
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Nozu, K, Nozu, Y, Nakanishi, K, Konomoto, T, Horinouchi, T, Shono, A, Morisada, N, Minamikawa, S, Yamamura, T, Fujimura, J, Nakanishi, K, Ninchoji, T, Kaito, H, Morioka, I, Ikeda, M, Vorechovsky, I & Iijima, K 2017, 'Cryptic exon activation in SLC12A3 in Gitelman syndrome', Journal of Human Genetics, vol. 62, no. 2, pp. 335-337. https://doi.org/10.1038/jhg.2016.129

Cryptic exon activation in SLC12A3 in Gitelman syndrome. / Nozu, Kandai; Nozu, Yoshimi; Nakanishi, Keita; Konomoto, Takao; Horinouchi, Tomoko; Shono, Akemi; Morisada, Naoya; Minamikawa, Shogo; Yamamura, Tomohiko; Fujimura, Junya; Nakanishi, Koichi; Ninchoji, Takeshi; Kaito, Hiroshi; Morioka, Ichiro; Ikeda, Mariko; Vorechovsky, Igor; Iijima, Kazumoto.

In: Journal of Human Genetics, Vol. 62, No. 2, 01.02.2017, p. 335-337.

Research output: Contribution to journalArticle

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AU - Nozu, Kandai

AU - Nozu, Yoshimi

AU - Nakanishi, Keita

AU - Konomoto, Takao

AU - Horinouchi, Tomoko

AU - Shono, Akemi

AU - Morisada, Naoya

AU - Minamikawa, Shogo

AU - Yamamura, Tomohiko

AU - Fujimura, Junya

AU - Nakanishi, Koichi

AU - Ninchoji, Takeshi

AU - Kaito, Hiroshi

AU - Morioka, Ichiro

AU - Ikeda, Mariko

AU - Vorechovsky, Igor

AU - Iijima, Kazumoto

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N2 - Gitelman syndrome (GS) is an autosomal recessive renal tubulopathy characterized by hypokalemic metabolic alkalosis with hypocalciuria and hypomagnesemia. GS clinical symptoms range from mild weakness to muscular cramps, paralysis or even sudden death as a result of cardiac arrhythmia. GS is caused by loss-of-function mutations in the solute carrier family 12 member 3 (SLC12A3) gene, but molecular mechanisms underlying such a wide range of symptoms are poorly understood. Here we report cryptic exon activation in SLC12A3 intron 12 in a clinically asymptomatic GS, resulting from an intronic mutation c.1669+297 T>G that created a new acceptor splice site. The cryptic exon was sandwiched between the L3 transposon upstream and a mammalian interspersed repeat downstream, possibly contributing to inclusion of the cryptic exon in mature transcripts. The mutation was identified by targeted next-generation sequencing of candidate genes in GS patients with missing pathogenic SLC12A3 alleles. Taken together, this work illustrates the power of next-generation sequencing to identify causal mutations in intronic regions in asymptomatic individuals at risk of developing potentially fatal disease complications, improving clinical management of these cases.

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Nozu K, Nozu Y, Nakanishi K, Konomoto T, Horinouchi T, Shono A et al. Cryptic exon activation in SLC12A3 in Gitelman syndrome. Journal of Human Genetics. 2017 Feb 1;62(2):335-337. https://doi.org/10.1038/jhg.2016.129