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Genes 2018, 9(1), 15; doi:10.3390/genes9010015

Splicing Analysis of Exonic OCRL Mutations Causing Lowe Syndrome or Dent-2 Disease

Unidad de Investigación, Hospital Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain
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Received: 9 November 2017 / Revised: 11 December 2017 / Accepted: 27 December 2017 / Published: 4 January 2018
(This article belongs to the Special Issue Aberrant Pre-mRNA Splicing in Disease)
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Abstract

Mutations in the OCRL gene are associated with both Lowe syndrome and Dent-2 disease. Patients with Lowe syndrome present congenital cataracts, mental disabilities and a renal proximal tubulopathy, whereas patients with Dent-2 disease exhibit similar proximal tubule dysfunction but only mild, or no additional clinical defects. It is not yet understood why some OCRL mutations cause the phenotype of Lowe syndrome, while others develop the milder phenotype of Dent-2 disease. Our goal was to gain new insights into the consequences of OCRL exonic mutations on pre-mRNA splicing. Using predictive bioinformatics tools, we selected thirteen missense mutations and one synonymous mutation based on their potential effects on splicing regulatory elements or splice sites. These mutations were analyzed in a minigene splicing assay. Results of the RNA analysis showed that three presumed missense mutations caused alterations in pre-mRNA splicing. Mutation c.741G>T; p.(Trp247Cys) generated splicing silencer sequences and disrupted splicing enhancer motifs that resulted in skipping of exon 9, while mutations c.2581G>A; p.(Ala861Thr) and c.2581G>C; p.(Ala861Pro) abolished a 5′ splice site leading to skipping of exon 23. Mutation c.741G>T represents the first OCRL exonic variant outside the conserved splice site dinucleotides that results in alteration of pre-mRNA splicing. Our results highlight the importance of evaluating the effects of OCRL exonic mutations at the mRNA level. View Full-Text
Keywords: OCRL gene; exonic mutation; splicing mutation; missense mutation; splice defects; exon skipping; minigene assay; bioinformatics tools; Lowe syndrome; Dent-2 disease OCRL gene; exonic mutation; splicing mutation; missense mutation; splice defects; exon skipping; minigene assay; bioinformatics tools; Lowe syndrome; Dent-2 disease
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Suarez-Artiles, L.; Perdomo-Ramirez, A.; Ramos-Trujillo, E.; Claverie-Martin, F. Splicing Analysis of Exonic OCRL Mutations Causing Lowe Syndrome or Dent-2 Disease. Genes 2018, 9, 15.

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