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 alpha4 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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigen-Antibody Complex
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Binding Sites
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Blotting, Western
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COS Cells
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Fibroblasts
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Fluorescent Antibody Technique
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Humans
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Ligases / genetics*
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Ligases / immunology
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Ligases / metabolism*
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Microtubule Proteins*
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Microtubule-Associated Proteins / genetics
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Microtubule-Associated Proteins / metabolism
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Microtubules / chemistry
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Microtubules / metabolism
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Models, Biological
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Mutation*
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Nuclear Proteins*
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Phosphoprotein Phosphatases / chemistry
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Phosphoprotein Phosphatases / metabolism*
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Phosphorylation
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Polyubiquitin / metabolism
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Precipitin Tests
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Protein Binding
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Protein Phosphatase 2
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Protein Subunits
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Substrate Specificity
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Syndrome
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Transcription Factors / genetics*
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Transcription Factors / immunology
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Transcription Factors / metabolism*
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Two-Hybrid System Techniques
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Ubiquitin / metabolism
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Ubiquitin-Protein Ligases
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Up-Regulation
Substances
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Antigen-Antibody Complex
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Microtubule Proteins
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Microtubule-Associated Proteins
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Nuclear Proteins
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Protein Subunits
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Transcription Factors
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Ubiquitin
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Polyubiquitin
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MID1 protein, human
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Ubiquitin-Protein Ligases
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Phosphoprotein Phosphatases
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Protein Phosphatase 2
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Ligases