TY - JOUR
T1 - Cryptic exon activation in SLC12A3 in Gitelman syndrome
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 - Taniguchi-Ikeda, Mariko
AU - Vorechovsky, Igor
AU - Iijima, Kazumoto
N1 - Funding Information:
This study was supported by a grant from the Ministry of Health, Labour and Welfare (Japan) for Research on Rare Intractable Diseases in the Kidney and Urinary Tract (H24-nanchitou (nan)-ippan-041 to Kazumoto Iijima) in the 'Research on Measures for Intractable Diseases' Project, and a Grant-in-Aid for Scientific Research (KAKENHI) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (subject ID: 25893131 to KN and 26293203 to KI).
Publisher Copyright:
© 2017 The Japan Society of Human Genetics All rights reserved.
PY - 2017/2/1
Y1 - 2017/2/1
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.
AB - 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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U2 - 10.1038/jhg.2016.129
DO - 10.1038/jhg.2016.129
M3 - Article
C2 - 27784896
AN - SCOPUS:85010911867
SN - 1434-5161
VL - 62
SP - 335
EP - 337
JO - Jinrui idengaku zasshi. The Japanese journal of human genetics
JF - Jinrui idengaku zasshi. The Japanese journal of human genetics
IS - 2
ER -