Abstract
Introduction: Two distinct phenotypes of Dent disease-2 and Lowe syndrome are caused by oculocerebrorenal syndrome of Lowe (OCRL) abnormality. Previous genetic studies demonstrated that truncating variants in exons 1 to 7 results in Dent disease-2 and in exons 8 to 24, result in Lowe syndrome. Recently, we successfully identified a functional OCRL isoform, whose altered initiation codons (Met187 and Met206) in exon 8 can affect the OCRL-truncating variant phenotypes. However, the association between OCRL splicing variants and phenotypes is poorly understood. Methods: We performed a detailed splicing pattern analysis of previously reported 28 OCRL splicing variants obtained from the Human Gene Mutation Database. We assessed the variant consequences at the mRNA level using an in vitro splicing assay with a minigene system, and examined their compatibility with in silico algorithms and correlation with disease phenotypes. Results: Aberrant splicing was confirmed in all 27 variants, except for 1, in which splicing could not be experimentally confirmed in the minigene system, and therefore could not be concluded with certainty. Splicing variants in OCRL exons 1 to 7 resulted in Dent disease-2, and in exons 9 to 24 resulted in Lowe syndrome. In 1 case, c.561-2 A > G in exon 8 demonstrated Dent disease-2. Conclusion: This study provides significant data on the pathogenicity of OCRL splicing variants and genotype-phenotype correlations. In c.561-2 A > G, the latter altered initiation codon of the OCRL isoform (Met206) was preserved, potentially indicating the Dent disease-2 phenotype. This result supports our recent finding regarding the altered initiation codons in exon 8 of the OCRL isoform.