Gitelman's syndrome is a mild autosomal recessive disorder caused by inactivating mutations of SLC12A3. However, severe phenotype may be associated with compound heterozygous nonfunctional variants such as frameshift and splicing mutations. Because most multi-exon genes are alternatively spliced as shown by recent studies, SLC12A3, with 26 exons, is likely to be alternatively spliced as well.A case of Gitelman's syndrome with both physical and mental retardation was investigated by genetic analysis. In addition, the alternative splice variants of SLC12A3 were screened by RT-PCR.A novel intron 7 and exon 8 boundary mutation (a successive 13-nucleotide transition: intron 7 as -1 G>A plus exon 8 +1 to +12 delCGGACATTTTTGinsCCGAAAATTTT) was identified in this patient besides a missense mutation Thr60Met. Further cDNA analysis revealed the novel mutation led to skipping of exons 7 and 8. Furthermore, we found an aberrant splice product skipping of exon 7 and identified two high-abundance alternative splice transcripts.This is the first report of a splice mutation of SLC12A3 with multiple-exon skipping in Gitelman's syndrome. This study provides further evidence for the severe phenotype of Gitelman's syndrome and its association with underlying mutations. Additionally, we demonstrated that the pre-mRNA of SLC12A3 was complex spliced.

作者：Leping, Shao；Liqiu, Liu；Zhimin, Miao；Hong, Ren；Weiming, Wang；Yanhua, Lang；Shaoheng, Yue；Nan, Chen

来源：American journal of nephrology 2008 年 28卷 6期