Biomedicines · 5 authors, 3 centres
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This study analyzed thirteen patients with suspected Dent disease and used minigene assays to test the splicing effects of identified and literature-known variants in the CLCN5 and OCRL genes. The functional analysis confirmed that three exonic missense mutations and two intronic variants disrupt pre-mRNA splicing.
Clinical assessment revealed tubular proteinuria in all patients, hypercalciuria in ten, and nephrolithiasis or nephrocalcinosis in five. Genetic analysis identified variants in CLCN5 (nine patients) and OCRL (four patients), with eight being novel. Fifteen variants with predicted splicing effects were tested using minigene assays in COS7 and HEK293T cells. Results showed that three exonic missense variants (c.1535G>A, c.1537G>A, c.1641G>T in CLCN5) and two intronic canonical splice site variants (c.1056+1G>A, c.1467-1G>A in OCRL) alter splicing. Specifically, two CLCN5 variants generate exonic splicing silencers leading to exon 10 skipping, while another causes skipping of exons 10 and 11. One OCRL variant results in exon 11 skipping, and the other leads to incorporation of a truncated exon 15. The study expands the genotypic spectrum of Dent disease and demonstrates the importance of functional assays for characterizing splicing defects.
