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

Genes
Lorena Suarez-ArtilesFelix Claverie-Martin

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 represent...Continue Reading

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Citations

Sep 21, 2018·Frontiers in Endocrinology·Claire GoursaudFlorence Roucher-Boulez
Mar 19, 2019·Intractable & Rare Diseases Research·Felix Claverie-MartinAlicia Callejon Callejon
Sep 30, 2021·Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association·Nana SakakibaraKandai Nozu

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Methods Mentioned

BETA
PCR
Transfection
Assay
electrophoresis

Software Mentioned

FAS
Primer BLAST
FASS
MutPred
NNSplice
HSF
Rescue ESE
SPANR
MutPred Splice
ESE Finder

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