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MID1, mutated in Opitz syndrome, encodes an ubiquitin ligase that targets phosphatase 2A for degradation

Nature Genetics volume 29, pages 287–294 (2001)Cite this article

An Erratum to this article was published on 01 January 2002

Abstract

The gene MID1, the mutation of which causes X-linked Opitz G/BBB syndrome (OS, MIM 300000), encodes a microtubule-associated protein (MAP). We show that mutation of MID1 leads to a marked accumulation of the catalytic subunit of protein phosphatase 2A (PP2Ac), a central cellular regulator. PP2Ac accumulation is caused by an impairment of a newly identified E3 ubiquitin ligase activity of the MID1 protein that normally targets PP2Ac for degradation through binding to its α4 regulatory subunit in an embryonic fibroblast line derived from a fetus with OS. Elevated PP2Ac causes hypophosphorylation of MAPs, a pathological mechanism that is consistent with the OS phenotype.

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Figure 1: Association of MID1 with polyubiquinated proteins.
Figure 2: Yeast two-hybrid analyses of MID1-a4 interactions.
Figure 3: The MID1–α4 interaction in COS-7 cells.
Figure 4: Regulation of PP2A by ubiquitin-mediated proteolysis in embryonic fibroblasts.
Figure 5: Dependence of PP2Ac quantity on MID1 expression.
Figure 6: Hypophosphorylation of microtubule-associated proteins in OS-derived embryonic fibroblasts.
Figure 7: Hypothetical model of the MID1-mediated ubiquitin-dependent regulation pathway of PP2A and its disruption in OS.

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Acknowledgements

We thank H. Madle and S. Freier for tissue culturing, V. Kalscheuer and B. Auer for their continuous support and helpful discussions, F. Fresser and G. Baier for their excellent support concerning the yeast two-hybrid methodology, K. Wrogemann for the correction of the manuscript and F. Erdogan for computer support. This work was supported by the Austrian National Bank Project 7961 (to R.S.) and by the Deutsche Forschungsgemeinschaft (DFG) Grant RO389/17-3 (to H.H.R.). This article is dedicated to M. Schweiger on the occasion of his 65th birthday.

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  1. Institute of Biochemistry, Peter-Mayr-Strasse 1a, Innsbruck, 6020, Austria

    Alexander Trockenbacher & Rainer Schneider

  2. Max-Planck Institute for Molecular Genetics, Ihnestrasse 73, Berlin, 14195, Germany

    Vanessa Suckow, Jennifer Winter, Sybille Krauß, Hans-Hilger Ropers & Susann Schweiger

  3. Department of Dermatology, Charite, Schuhmannstrasse 20–22, Berlin, 10117, Germany

    John Foerster

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Correspondence to Susann Schweiger.

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Trockenbacher, A., Suckow, V., Foerster, J. et al. MID1, mutated in Opitz syndrome, encodes an ubiquitin ligase that targets phosphatase 2A for degradation. Nat Genet 29, 287–294 (2001). https://doi.org/10.1038/ng762

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