title: Cryptic exon activation in SLC12A3 in Gitelman syndrome.
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.
authors: Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan.
authors: Kandai
authors: K
authors: Nozu
authors: Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan.
authors: Yoshimi
authors: Y
authors: Nozu
authors: Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan.
authors: Keita
authors: K
authors: Nakanishi
authors: Department of Pediatrics, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
authors: Takao
authors: T
authors: Konomoto
authors: Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan.
authors: Tomoko
authors: T
authors: Horinouchi
authors: Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan.
authors: Akemi
authors: A
authors: Shono
authors: Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan.
authors: Naoya
authors: N
authors: Morisada
authors: Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan.
authors: Shogo
authors: S
authors: Minamikawa
authors: Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan.
authors: Tomohiko
authors: T
authors: Yamamura
authors: Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan.
authors: Junya
authors: J
authors: Fujimura
authors: Department of Pediatrics, Wakayama Medical University, Wakayama, Japan.
authors: Koichi
authors: K
authors: Nakanishi
authors: Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan.
authors: Takeshi
authors: T
authors: Ninchoji
authors: Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan.
authors: Hiroshi
authors: H
authors: Kaito
authors: Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan.
authors: Ichiro
authors: I
authors: Morioka
authors: Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan.
authors: Mariko
authors: M
authors: Taniguchi-Ikeda
authors: University of Southampton Faculty of Medicine, Southampton, UK.
authors: Igor
authors: I
authors: Vorechovsky
authors: Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan.
authors: Kazumoto
authors: K
authors: Iijima
mesh_terms: D001483:Base Sequence; D002675:Child, Preschool; D005091:Exons / Q000235:genetics; D005260:Female; D053579:Gitelman Syndrome / Q000175:diagnosis* / Q000235:genetics* / Q000473:pathology; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007438:Introns / Q000235:genetics; D007686:Kidney Tubules, Distal / Q000473:pathology*; D009154:Mutation / Q000235:genetics; D017422:Sequence Analysis, DNA; D064486:Solute Carrier Family 12, Member 3 / Q000235:genetics / Q000378:metabolism
chemical_list: C578874:SLC12A3 protein, human; D064486:Solute Carrier Family 12, Member 3