Abstract
Background
Approximately 15% of patients with Dent disease have pathogenic variants in the OCRL gene on Xq25-26, a condition that is referred to as Dent disease 2 (Dent-2). Dent-2 patients sometimes show mild extrarenal features of Lowe syndrome, such as mild mental retardation, suggesting that Dent-2 represents a mild form of Lowe syndrome. To date, eight female patients with Lowe syndrome have been reported, but no female Dent-2 patients have been reported.
Methods
In this study, we performed genetic testing of the first female Dent-2 patient to detect the presence of an OCRL variant. Aberrant splicing was demonstrated by in vivo, in vitro, and in silico assays, and skewed X-chromosome inactivation (XCI) in our patient and asymptomatic mothers of three Lowe patients with the heterozygous OCRL variant was evaluated by HUMARA assays using genomic DNA and RNA expression analysis.
Results
Our patient had an OCRL heterozygous intronic variant of c.1603-3G > C in intron 15 that led to a 169-bp insertion in exon 16, yielding the truncating mutation r.1602_1603ins (169) (p.Val535Glyfs*6) in exon 16. HUMARA assays of leukocytes obtained from this patient demonstrated incompletely skewed XCI (not extremely skewed). On the other hand, the asymptomatic mothers of 3 Lowe patients demonstrated random XCI. These results may lead to our patient’s Dent-2 phenotype.
Conclusions
This is the first report of a female patient clinically and genetically diagnosed with Dent-2 caused by an OCRL heterozygous splicing site variant and skewed XCI. Skewed XCI may be one of the factors associated with phenotypic diversity in female patients with Lowe syndrome and Dent-2.
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Acknowledgements
This study was supported by Grants-in-Aid for Scientific Research (KAKENHI) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (subject ID: 19K17297 to Nana Sakakibara, 17H04189 to Kazumoto Iijima and 19K08726 to Kandai Nozu). The authors thank Ichiro Kobayashi and Yukiyo Ohshima (Department of Pediatrics, KKR Sapporo Medical Center, Sapporo, Japan) for providing us with medical information on the patient and her family. they also thank Tomohiko Yamamura and Tomoko Horinouchi (Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan) for conducting the genetic examination. They thank American Journal Experts for editing a draft of this manuscript.
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Our patient is a patient at Hokkaido University Hospital and this analysis was performed at Kobe University Graduate School of Medicine. All procedures performed in this study were reviewed and approved by the Institutional Review Board of Hokkaido University Hospital (IRB approval number 019–0412) and Kobe University Graduate School of Medicine (IRB approval number 019–301).
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10157_2020_1926_MOESM1_ESM.pdf
Supplementary file1 (PDF 3385 kb) Figure 1. The de novo mutation in our patient is located on the paternal X chromosome a.In intron 17 of the OCRL gene, the mother had a benign variant (c.1879+38_1879+39insTCC, dBSNP:rs34007381), while the father did not have this benign variant. b.Genetic analysis of our patient demonstrated that this benign variant was not found in the allele with the de novo mutation in intron 15 that was separated by subcloning of the purified PCR products.
10157_2020_1926_MOESM2_ESM.pdf
Supplementary file2 (PDF 6300 kb) Figure 2. Relationship between the degree of skewedness of X-chromosome inactivation and clinical severity in female cases with heterozygous OCRL mutations a.Clinical and genetic characteristics of 3 Lowe patients whose mothers have heterozygous OCRL mutations. b.XCI analysis by HUMARA assay in peripheral leukocytes in the mothers of 3 Lowe patients with the heterozygous OCRL variant. All of them demonstrated no skewed XCI. c.Summary of XCI in female cases with heterozygous OCRL mutation.
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Okamoto, T., Sakakibara, N., Nozu, K. et al. Onset mechanism of a female patient with Dent disease 2. Clin Exp Nephrol 24, 946–954 (2020). https://doi.org/10.1007/s10157-020-01926-4
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DOI: https://doi.org/10.1007/s10157-020-01926-4