Letter | Published:

Radixin deficiency causes conjugated hyperbilirubinemia with loss of Mrp2 from bile canalicular membranes

Nature Genetics volume 31, pages 320325 (2002) | Download Citation

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Abstract

The ezrin-radixin-moesin (ERM) family of proteins crosslink actin filaments and integral membrane proteins1,2,3. Radixin (encoded by Rdx) is the dominant ERM protein in the liver of wildtype mice4,5 and is concentrated at bile canalicular membranes (BCMs)5. Here we show that Rdx−/− mice are normal at birth, but their serum concentrations of conjugated bilirubin begin to increase gradually around 4 weeks, and they show mild liver injury after 8 weeks. This phenotype is similar to human conjugated hyperbilirubinemia in Dubin-Johnson syndrome6,7, which is caused by mutations in the multidrug resistance protein 2 (MRP2, gene symbol ABCC2)8,9,10,11, although this syndrome is not associated with overt liver injury. In wildtype mice, Mrp2 concentrates at BCMs to secrete conjugated bilirubin into bile8,11,12. In the BCMs of Rdx−/− mice, Mrp2 is decreased compared with other BCM proteins such as dipeptidyl peptidase IV (CD26) and P-glycoproteins. In vitro binding studies show that radixin associates directly with the carboxy-terminal cytoplasmic domain of human MRP2. These findings indicate that radixin is required for secretion of conjugated bilirubin through its support of Mrp2 localization at BCMs.

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GenBank/EMBL/DDBJ

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Acknowledgements

We thank T. Noda for discussions and J. Yamane for preparing bile canalicular fractions. This work was supported in part by a Grant-in-Aid for Scientific Research (B) (to Sa.T.) and a Grant-in-Aid for Cancer Research (to Sh.T.) from the Ministry of Education, Science and Culture of Japan, and grants from the Deutsche Forschunggemeinshaft (to D.K.).

Author information

Author notes

    • Shojiro Kikuchi
    •  & Masaki Hata

    These authors contributed equally to this work.

Affiliations

  1. Department of Cell Biology, Faculty of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.

    • Shojiro Kikuchi
    • , Kanehisa Fukumoto
    • , Yukari Yamane
    • , Takeshi Matsui
    • , Atsushi Tamura
    • , Shoichiro Tsukita
    •  & Sachiko Tsukita
  2. Department of Surgery, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto 602-8566, Japan.

    • Shojiro Kikuchi
    • , Kanehisa Fukumoto
    •  & Hisakazu Yamagishi
  3. KAN Research Institute, Kyoto Research Park, Shimogyo-ku, Kyoto 600-8815, Japan.

    • Masaki Hata
    •  & Takeshi Matsui
  4. Laboratory for Cellular Morphogenesis, RIKEN Center for Developmental Biology, Chuo-ku, Kobe 650-0047, Japan.

    • Shigenobu Yonemura
  5. Division of Tumor Biochemistry, Deutsches Krebsforschungszentrum, D-69120 Heidelberg, Germany.

    • Dietrich Keppler
  6. College of Medical Technology, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan.

    • Sachiko Tsukita

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The authors declare no competing financial interests.

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Correspondence to Sachiko Tsukita.

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DOI

https://doi.org/10.1038/ng905

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