Onset mechanism of a female patient with Dent disease 2
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ORIGINAL ARTICLE
Onset mechanism of a female patient with Dent disease 2 Takayuki Okamoto1 · Nana Sakakibara2 · Kandai Nozu2 · Toshiyuki Takahashi1 · Asako Hayashi1 · Yasuyuki Sato1 · China Nagano2 · Masafumi Matsuo3 · Kazumoto Iijima2 · Atsushi Manabe1 Received: 23 April 2020 / Accepted: 23 June 2020 © Japanese Society of Nephrology 2020
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. Keywords Lowe syndrome · Dent disease · X-chromosome inactivation · OCRL · Genetic counseling
Introduction
Takayuki Okamoto and Nana Sakakibara contributed equally to this study. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10157-020-01926-4) contains supplementary material, which is available to authorized users. * Takayuki Okamoto [email protected] 1
Department of Pediatrics, Hokkaido University Graduate School of Medicine, North 15, West 7, Sapporo, Hokkaido 060‑8638, Japan
2
Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Hyogo 650‑0017, Japan
3
Department of Physical Therapy, Faculty of Rehabilitation, Kobe Gakuin University, Kobe, Hyogo 651‑2180, Japan
The classic form of oculocerebrorenal syndrome of Lowe (Lowe syndrome; OMIM#309000) is an X-linked multisystemic disorder characterized by the triad of congenital cataracts, severe intellectual impairment, and renal proximal tubular dysfunction that usually leads t
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