Comprehensive Splice Pattern Analysis for Previously Reported Splicing Variants and Their Phenotypic Contributions.

INTRODUCTION

Two distinct phenotypes of Dent disease-2 and Lowe syndrome are caused by () 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 isoform, whose altered initiation codons (Met187 and Met206) in exon 8 can affect the -truncating variant phenotypes. However, the association between splicing variants and phenotypes is poorly understood.

METHODS

We performed a detailed splicing pattern analysis of previously reported 28 splicing variants obtained from the Human Gene Mutation Database. We assessed the variant consequences at the mRNA level using an splicing assay with a minigene system, and examined their compatibility with 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 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 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.