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Incomplete cryptic splicing by an intronic mutation of OCRL in patients with partial phenotypes of Lowe syndrome


Mutations of OCRL cause Lowe syndrome, which is characterised by congenital cataracts, infantile hypotonia with mental retardation, and renal tubular dysfunction and Dent-2 disease, which only affects the kidney. While few patients with an intermediate phenotype between these diseases have been reported, the mechanism underlying variability in the phenotype is unclear. We identified an intronic mutation, c.2257-5G>A, in intron 20 of OCRL in an older brother with atypical Lowe syndrome without eye involvement and a younger brother with renal phenotype alone. This mutation created a splice acceptor motif that was accompanied by a cryptic premature termination codon at the junction of exons 20 and 21. The mutation caused incomplete alternative splicing, which created a small amount of wild-type transcript and a relatively large amount of alternatively spliced transcript with a premature termination codon. In the patients’ cells, the alternatively spliced transcript was degraded by nonsense-mediated decay and the wild-type transcript was significantly decreased, but not completely depleted. These findings imply that an intronic mutation creating an incomplete alternative splicing acceptor site results in a relatively low level of wild-type OCRL mRNA expression, leading to partial phenotypes of Lowe syndrome.

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Fig. 1: OCRL mutation in the affected brothers.
Fig. 2: Minigene assay and direct sequencing of the transcript of OCRL.
Fig. 3: mRNA containing a PTC was degraded by NMD in vivo.
Fig. 4: Quantitation of OCRL mRNA transcripts from patients and controls using whole blood (left) and urine sediments (right).
Fig. 5: Schematic diagram of incomplete OCRL splicing, which causes an intermediate phenotype between Lowe syndrome and Dent-2 disease.

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  1. Suchy SF, Nussbaum RL. The deficiency of PIP2 5-phosphatase in Lowe syndrome affects actin polymerization. Am J Hum Genet. 2002;71:1420–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. De Matteis MA, Staiano L, Emma F, Devuyst O. The 5-phosphatase OCRL in Lowe syndrome and Dent disease 2. Nat Rev Nephrol. 2017;13:455–70.

    Article  CAS  PubMed  Google Scholar 

  3. Hoopes RR, Shrimpton AE, Knohl SJ, Hueber P, Hoppe B, Matyus J, et al. Dent disease with mutations in OCRL1. Am J Hum Genet. 2005;76:260–7.

    Article  CAS  PubMed  Google Scholar 

  4. Bökenkamp A, Ludwig M. The oculocerebrorenal syndrome of Lowe: an update. Pediatr Nephrol. 2016;31:2201–12.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Recker F, Zaniew M, Böckenhauer D, Miglietti N, Bökenkamp A, Moczulska A, et al. Characterization of 28 novel patients expands the mutational and phenotypic spectrum of Lowe syndrome. Pediatr Nephrol. 2015;30:931–43.

    Article  PubMed  Google Scholar 

  6. Hichri H, Rendu J, Monnier N, Coutton C, Dorseuil O, Poussou RV, et al. From lowe syndrome to Dent disease: correlations between mutations of the OCRL1 gene and clinical and biochemical phenotypes. Hum Mutat. 2011;32:379–88.

    Article  CAS  PubMed  Google Scholar 

  7. Mario Loi. Lowe syndrome. Orphanet J Rare Dis. 2006;1:16.

    Article  Google Scholar 

  8. Schneider JFL, Boltshauser E, Neuhaus TJ, Rauscher C, Martin E. MRI and proton spectroscopy in Lowe syndrome. Neuropediatrics. 2001;32:45–8.

    Article  CAS  PubMed  Google Scholar 

  9. Bockenhauer D, Bokenkamp A. van’t Hoff W, Levtchenko E, Kist-van Holthe JE, Tasic V, et al. Renal phenotype in Lowe syndrome: a selective proximal tubular dysfunction. Clin J Am Soc Nephrol. 2008;3:1430–6.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Dent CE, Friedman M. Hypercalcuric rickets associated with renal tubular damage. Arch Dis Child. 1964;39:240–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Thakker RV. Pathogenesis of Dent’s disease and related syndromes of X-linked nephrolithiasis. Kidney Int. 2000;57:787–93.

    Article  CAS  PubMed  Google Scholar 

  12. Shrimpton AE, Hoopes RR, Knohl SJ, Hueber P, Reed AAC, Christie PT, et al. OCRL1 mutations in dent 2 patients suggest a mechanism for phenotypic variability. Nephron - Physiol. 2009;112:27–36.

    Article  CAS  Google Scholar 

  13. Tosetto E, Addis M, Caridi G, Meloni C, Emma F, Vergine G, et al. Locus heterogeneity of Dent’s disease: OCRL1 and TMEM27 genes in patients with no CLCN5 mutations. Pediatr Nephrol. 2009;24:1967–73.

    Article  PubMed  Google Scholar 

  14. Jefferson AB, Majerus PW. Properties of type II inositol polyphosphate 5-phosphatase. J Biol Chem. 1995;270:9370–7.

    Article  CAS  PubMed  Google Scholar 

  15. Inoue K, Balkin DM, Liu L, Nandez R, Wu Y, Tian X, et al. Kidney tubular ablation of Ocrl/Inpp5b phenocopies lowe syndrome tubulopathy. J Am Soc Nephrol. 2017;28:1399–407.

    Article  CAS  PubMed  Google Scholar 

  16. Montjean R, Aoidi R, Desbois P, Rucci J, Trichet M, Salomon R, et al. OCRL-mutated fibroblasts from patients with Dent-2 disease exhibit INPP5B-independent phenotypic variability relatively to Lowe syndrome cells. Hum Mol Genet. 2015;24:994–1006.

    Article  CAS  PubMed  Google Scholar 

  17. Burset M. Analysis of canonical and non-canonical splice sites in mammalian genomes. Nucleic Acids Res. 2000;28:4364–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Lykke-Andersen S, Jensen TH. Nonsense-mediated mRNA decay: An intricate machinery that shapes transcriptomes. Nat Rev Mol Cell Biol. 2015;16:665–77.

    Article  CAS  PubMed  Google Scholar 

  19. Pasternack SM, Böckenhauer D, Refke M, Tasic V, Draaken M, Conrad C, et al. A premature termination mutation in a patient with lowe syndrome without congenital cataracts: Dropping the “O” in OCRL. Klin Padiatr. 2013;225:29–33.

    PubMed  CAS  Google Scholar 

  20. Bökenkamp A, Böckenhauer D, Cheong H,II, Hoppe B, Tasic V, Unwin R. et al. Dent-2 disease: a mild variant of lowe syndrome. J Pediatr. 2009;155:94–9.

    Article  PubMed  Google Scholar 

  21. Böckenhauer D, Bökenkamp A, Nuutinen M, Unwin R, Van’t Hoff W, Sirimanna T, et al. Novel OCRL mutations in patients with Dent-2 disease. J Pediatr Genet. 2012;1:15–23.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Kurosaki T, Maquat LE. Nonsense-mediated mRNA decay in humans at a glance. J Cell Sci. 2016;129:461–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Nakanishi K, Nozu K, Hiramoto R, Minamikawa S, Yamamura T, Fujimura J, et al. A comparison of splicing assays to detect an intronic variant of the OCRL gene in Lowe syndrome. Eur J Med Genet. 2017;60:631–4.

    Article  PubMed  Google Scholar 

  24. Rendu J, Montjean R, Coutton C, Suri M, Chicanne G, Petiot A, et al. Functional characterization and rescue of a deep intronic mutation in OCRL gene responsible for Lowe syndrome. Hum Mutat. 2017;38:152–9.

    Article  CAS  PubMed  Google Scholar 

  25. Monnier N, Satre V, Lerouge E, Berthoin F, Lunardi J. OCRL1 mutation analysis in french lowe syndrome patients: Implications for molecular diagnosis strategy and genetic counseling. Hum Mutat. 2000;16:157–65.

    Article  CAS  PubMed  Google Scholar 

  26. Addis M, Loi M, Lepiani C, Cau M, Melis MA. OCRL mutation analysis in Italian patients with Lowe syndrome. Hum Mutat. 2004;23:524–5.

    Article  CAS  PubMed  Google Scholar 

  27. Sethi SK, Bagga A, Gulati A, Hari P, Gupta N, Lunardi J. Mutations in OCRL1 gene in Indian children with Lowe syndrome. Clin Exp Nephrol. 2008;12:358–62.

    Article  CAS  PubMed  Google Scholar 

  28. Ono H, Saitsu H, Horikawa R, Nakashima S, Ohkubo Y, Yanagi K, et al. Partial androgen insensitivity syndrome caused by a deep intronic mutation creating an alternative splice acceptor site of the AR gene. Sci Rep. 2018;8:4–11.

    Article  CAS  Google Scholar 

  29. Highsmith WE, Burchl LH, Zhou Z, Olsen JC, Boat TE, Spock A, et al. A novel mutation in the cystic fibrosis gene in patients with pulmonary disease but normal sweat chloride concentrations. N Engl J Med. 1994;331:974–80.

    Article  CAS  PubMed  Google Scholar 

  30. Chiba-Falek O, Kerem E, Shoshani T, Aviram M, Augarten A, Bentur L, et al. The molecular basis of disease variability among cystic fibrosis patients carrying the 3849+10 kb C→T mutation. Genomics. 1998;53:276–83.

    Article  CAS  PubMed  Google Scholar 

  31. Wang ET, Sandberg R, Luo S, Khrebtukova I, Zhang L, Mayr C, et al. Alternative isoform regulation in human tissue transcriptomes. Nature. 2008;456:470–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Pan Q, Shai O, Lee LJ, Frey BJ, Blencowe BJ. Deep surveying of alternative splicing complexity in the human transcriptome by high-throughput sequencing. Nat Genet. 2008;40:1413–5.

    Article  CAS  PubMed  Google Scholar 

  33. Ramirez IBR, Pietka G, Jones DR, Divecha N, Alia A, Baraban SC, et al. Impaired neural development in a zebrafish model for lowe syndrome. Hum Mol Genet. 2012;21:1744–59.

    Article  CAS  PubMed  Google Scholar 

  34. Oltrabella F, Pietka G, Ramirez IBR, Mironov A, Starborg T, Drummond IA, et al. The Lowe syndrome protein OCRL1 is required for endocytosis in the zebrafish Pronephric Tubule. PLoS Genet. 2015.

  35. de Klerk E, ’t Hoen PAC. Alternative mRNA transcription, processing, and translation: Insights from RNA sequencing. Trends Genet.2015;31:128–39.

    Article  CAS  PubMed  Google Scholar 

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This work was supported in part by a Grant-in-Aid for Scientific Research (C) [15K09682 to KM and YH, and 17K10157 to TY, KM and YH] from the Ministry of Education, Culture, Sports, Science and Technology of Japan and by a Health and Labour Sciences Research Grant [H27-037 to YH and KM, and H29-039 to YH] from the Ministry of Health, Labour and Welfare of Japan. We thank Ellen Knapp, PhD, and Ryan Chastain-Gross, PhD, from Edanz Group ( for editing a draft of this manuscript.

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Correspondence to Yutaka Harita.

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Nakano, E., Yoshida, A., Miyama, Y. et al. Incomplete cryptic splicing by an intronic mutation of OCRL in patients with partial phenotypes of Lowe syndrome. J Hum Genet 65, 831–839 (2020).

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