期刊
JOURNAL OF HUMAN GENETICS
卷 62, 期 2, 页码 335-337出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/jhg.2016.129
关键词
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资金
- Ministry of Health, Labour and Welfare (Japan) for Research on Rare Intractable Diseases in the Kidney and Urinary Tract in the 'Research on Measures for Intractable Diseases' Project [H24-nanchitou (nan)-ippan-041]
- Ministry of Education, Culture, Sports, Science and Technology of Japan [25893131, 26293203]
- Grants-in-Aid for Scientific Research [25893131, 26293203, 16K10066, 15K09261] Funding Source: KAKEN
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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