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

Abstract

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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Acknowledgements

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 (www.edanzediting.com/ac) for editing a draft of this manuscript.

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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). https://doi.org/10.1038/s10038-020-0773-3

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