Rossanti Rini, Okada Eri, Sakakibara Nana, Suzuki Ryota, Inoki Yuta, Ichikawa Yuta, Tanaka Yu, Kitakado Hideaki, Ueda Chika, Kondo Atsushi, Aoto Yuya, Nagano China, Horinouchi Tomoko, Yamamura Tomohiko, Ishimori Shingo, Nozu Kandai
Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan.
Department of Child Health, Nephrology Division, Dr. Hasan Sadikin General Hospital/Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia.
Kidney Int Rep. 2025 Mar 3;10(5):1509-1517. doi: 10.1016/j.ekir.2025.02.023. eCollection 2025 May.
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.
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.
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.
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.
Dent病2型和Lowe综合征这两种不同的表型是由（）异常引起的。先前的遗传学研究表明，外显子1至7中的截短变异导致Dent病2型，而外显子8至24中的截短变异导致Lowe综合征。最近，我们成功鉴定出一种功能性异构体，其外显子8中起始密码子（Met187和Met206）的改变会影响截短变异表型。然而，对于剪接变异与表型之间的关联了解甚少。
我们对从人类基因突变数据库中获取的先前报道的28个剪接变异进行了详细的剪接模式分析。我们使用带有微型基因系统的剪接试验在mRNA水平评估变异后果，并检查它们与算法的兼容性以及与疾病表型的相关性。
除1个变异外，所有27个变异均证实存在异常剪接，在微型基因系统中无法通过实验证实该变异的剪接情况，因此无法确定结论。外显子1至7中的剪接变异导致Dent病2型，外显子9至24中的剪接变异导致Lowe综合征。在1例中，外显子8中的c.561-2 A>G表现为Dent病2型。
本研究提供了关于剪接变异致病性以及基因型-表型相关性的重要数据。在c.561-2 A>G中，OCRL异构体（Met206）的后一个改变的起始密码子得以保留，这可能表明是Dent病2型表型。这一结果支持了我们最近关于OCRL异构体外显子8中起始密码子改变的发现。
