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Decreased urinary excretion of the ectodomain form of megalin (A-megalin) in children with OCRL gene mutations

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A Correction to this article was published on 18 January 2022

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Abstract

Background

The oculocerebrorenal syndrome of Lowe gene (OCRL) is located on chromosome Xq25-26 and encodes an inositol polyphosphate-5-phosphatase (OCRL-1). Mutations in this gene cause Lowe syndrome (LS) or type 2 Dent disease, of which low-molecular-weight (LMW) proteinuria is a characteristic feature. Megalin is considered to play an important role in the development of renal tubular proteinuria. Two forms of megalin are excreted into the urine: full-length megalin (C-megalin) and megalin ectodomain (A-megalin). We have explored the role of megalin in the development of LMW proteinuria in patients with OCRL mutations by determining urinary megalin fractions.

Methods

We measured A- and C-megalin in spot urine samples from five male patients with OCRL mutations (median age 9 years), using sandwich enzyme-linked immunosorbent assays, and adjusted the obtained values for excreted creatinine. The results were compared with those of 50 control subjects and one patient with type 1 Dent disease (T1D).

Results

All patients demonstrated normal levels of urinary C-megalin. However, patients with OCRL mutations or T1D showed abnormally low levels of urinary A-megalin, with the exception of one 5-year-old boy with LS, who was the youngest patient enrolled in the study.

Conclusions

Decreased excretion of urinary A-megalin in four out of five patients with OCRL mutations suggests that LMW proteinuria may be caused by impaired megalin recycling within the proximal tubular cells. Homologous enzymes, similar to inositol polyphosphate-5-phosphatase B in mice, may help to compensate for defective OCRL-1 function during early childhood.

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Acknowledgments

The authors are grateful to Prof. Takashi Igarashi, President of the National Center for Child Health and Development, Tokyo; Prof. Takashi Sekine (deceased), Toho University School of Medicine, Tokyo; and Dr. Kandai Nozu, Associate Professor, Department of Pediatrics, Kobe University School of Medicine, Hyogo, Japan. Urinary excretion of A- and C-megalin was measured by Denka Co. Ltd. This study was partly supported by the Mami Mizutani Foundation.

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Authors and Affiliations

  1. Department of Pediatrics, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka, 573-1010, Japan

    Chikushi Suruda, Shoji Tsuji, Sohsaku Yamanouchi, Takahisa Kimata & Kazunari Kaneko

  2. Division of Nephrology, 2nd Department of Internal Medicine, Kansai Medical University, Osaka, Japan

    Nguyen Thanh Huan & Hiroyasu Tsukaguchi

  3. Diagnostics Research Department, Life Innovation Research Institute, Denka Innovation Center, Denka Co. Ltd., Tokyo, Japan

    Hiroyuki Kurosawa & Yoshiaki Hirayama

  4. Department of Applied Molecular Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

    Akihiko Saito

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  1. Chikushi Suruda
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  2. Shoji Tsuji
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  3. Sohsaku Yamanouchi
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  4. Takahisa Kimata
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  5. Nguyen Thanh Huan
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  6. Hiroyuki Kurosawa
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  7. Yoshiaki Hirayama
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  8. Hiroyasu Tsukaguchi
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  9. Akihiko Saito
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  10. Kazunari Kaneko
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Corresponding author

Correspondence to Kazunari Kaneko.

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AS received research grants from DENKA Co. Ltd.

Research involving human participants

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from the parents of all individual participants included in the study.

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Suruda, C., Tsuji, S., Yamanouchi, S. et al. Decreased urinary excretion of the ectodomain form of megalin (A-megalin) in children with OCRL gene mutations. Pediatr Nephrol 32, 621–625 (2017). https://doi.org/10.1007/s00467-016-3535-x

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  • DOI: https://doi.org/10.1007/s00467-016-3535-x

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