Background: 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.
Methods: 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.
Results: 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.
Conclusion: 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.
Copyright 2008 S. Karger AG, Basel.