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

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...

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Autores principales: Suarez-Artiles, Lorena, Perdomo-Ramirez, Ana, Ramos-Trujillo, Elena, Claverie-Martin, Felix
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5793168/
https://www.ncbi.nlm.nih.gov/pubmed/29300302
http://dx.doi.org/10.3390/genes9010015
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author Suarez-Artiles, Lorena
Perdomo-Ramirez, Ana
Ramos-Trujillo, Elena
Claverie-Martin, Felix
author_facet Suarez-Artiles, Lorena
Perdomo-Ramirez, Ana
Ramos-Trujillo, Elena
Claverie-Martin, Felix
author_sort Suarez-Artiles, Lorena
collection PubMed
description 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.
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spelling pubmed-57931682018-02-07 Splicing Analysis of Exonic OCRL Mutations Causing Lowe Syndrome or Dent-2 Disease Suarez-Artiles, Lorena Perdomo-Ramirez, Ana Ramos-Trujillo, Elena Claverie-Martin, Felix Genes (Basel) Article 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. MDPI 2018-01-04 /pmc/articles/PMC5793168/ /pubmed/29300302 http://dx.doi.org/10.3390/genes9010015 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Suarez-Artiles, Lorena
Perdomo-Ramirez, Ana
Ramos-Trujillo, Elena
Claverie-Martin, Felix
Splicing Analysis of Exonic OCRL Mutations Causing Lowe Syndrome or Dent-2 Disease
title Splicing Analysis of Exonic OCRL Mutations Causing Lowe Syndrome or Dent-2 Disease
title_full Splicing Analysis of Exonic OCRL Mutations Causing Lowe Syndrome or Dent-2 Disease
title_fullStr Splicing Analysis of Exonic OCRL Mutations Causing Lowe Syndrome or Dent-2 Disease
title_full_unstemmed Splicing Analysis of Exonic OCRL Mutations Causing Lowe Syndrome or Dent-2 Disease
title_short Splicing Analysis of Exonic OCRL Mutations Causing Lowe Syndrome or Dent-2 Disease
title_sort splicing analysis of exonic ocrl mutations causing lowe syndrome or dent-2 disease
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5793168/
https://www.ncbi.nlm.nih.gov/pubmed/29300302
http://dx.doi.org/10.3390/genes9010015
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