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BiP inactivation due to loss of the deAMPylation function of FICD causes a motor neuron disease

  • Adriana P. Rebelo
    Affiliations
    Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL
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  • Ariel Ruiz
    Affiliations
    Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL
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  • Maike F. Dohrn
    Affiliations
    Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL

    Department of Neurology, Medical Faculty RWTH Aachen University, Aachen, Germany
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  • Melanie Wayand
    Affiliations
    Hertie Institute for Clinical Brain Research (HIH), Center of Neurology, University of Tübingen, Tübingen, Germany

    German Center for Neurodegenerative Diseases (DZNE), University of Tübingen, Tübingen, Germany
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  • Amjad Farooq
    Affiliations
    Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL
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  • Matt C. Danzi
    Affiliations
    Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL
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  • Danique Beijer
    Affiliations
    Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL
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  • Brooke Aaron
    Affiliations
    Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL
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  • Jana Vandrovcova
    Affiliations
    Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, United Kingdom
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  • Henry Houlden
    Affiliations
    Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, United Kingdom
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  • Leslie Matalonga
    Affiliations
    CNAG-CRG, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain
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  • Lisa Abreu
    Affiliations
    Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL
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  • Guy Rouleau
    Affiliations
    Department of Human Genetics, Faculty of Medicine and Health Sciences, McGill University, Montreal, Quebec, Canada

    The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montreal, Quebec, Canada

    Department of Neurology and Neurosurgery, Faculty of Medicine and Health Sciences, McGill University, Montreal, Quebec, Canada
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  • Mehrdad A. Estiar
    Affiliations
    Department of Human Genetics, Faculty of Medicine and Health Sciences, McGill University, Montreal, Quebec, Canada

    The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montreal, Quebec, Canada

    Department of Neurology and Neurosurgery, Faculty of Medicine and Health Sciences, McGill University, Montreal, Quebec, Canada
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  • Liedewei Van de Vondel
    Affiliations
    Translational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
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  • Ziv Gan-Or
    Affiliations
    Department of Human Genetics, Faculty of Medicine and Health Sciences, McGill University, Montreal, Quebec, Canada

    The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montreal, Quebec, Canada

    Department of Neurology and Neurosurgery, Faculty of Medicine and Health Sciences, McGill University, Montreal, Quebec, Canada
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  • Jonathan Baets
    Affiliations
    Translational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium

    Neuromuscular Reference Center, Antwerp University Hospital and Faculty of Medicine University of Antwerp, Antwerp, Belgium
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  • Rebecca Schüle
    Affiliations
    Hertie Institute for Clinical Brain Research (HIH), Center of Neurology, University of Tübingen, Tübingen, Germany

    German Center for Neurodegenerative Diseases (DZNE), University of Tübingen, Tübingen, Germany
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  • Stephan Zuchner
    Correspondence
    Correspondence and requests for materials should be addressed to Stephan Zuchner, Departments of Human Genetics and Neurology, University of Miami Miller School of Medicine, Biomedical Research Building (BRB), Room 616, LC: M-860, 1501 NW 10th Avenue, Miami, FL 33136
    Affiliations
    Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL
    Search for articles by this author
Published:September 22, 2022DOI:https://doi.org/10.1016/j.gim.2022.08.019

      ABSTRACT

      Purpose

      The chaperone protein BiP is the master regulator of the unfolded protein response in the endoplasmic reticulum. BiP chaperone activity is regulated by the post-translational modification AMPylation, exclusively provided by FICD. We investigated whether FICD variants identified in patients with motor neuron disease could interfere with BiP activity regulation.

      Methods

      Exome sequencing was performed to identify causative pathogenic variants associated with motor neuron diseases. Functional studies were conducted on fibroblasts from patients to explore the molecular mechanism of the disease.

      Results

      We identified biallelic variants in FICD causing a neurodegenerative disease of upper and lower motor neurons. Affected individuals harbor a specific missense variant, Arg374His, positioned in the catalytic motif of the enzyme and important for adenosine triphosphate binding. The mutated residue abolishes intramolecular interaction with the regulatory residue Glu234, essential to inhibit AMPylation and to promote de-AMPylation by FICD. Consequently, fibroblasts from patients with FICD variants have abnormally increased levels of AMPylated and thus inactivated BiP.

      Conclusion

      Loss of BiP chaperone activity in patients likely results in a chronic impairment of the protein quality control system in the endoplasmic reticulum. These findings will guide the development of therapeutic strategies for motoneuron and related diseases linked to proteotoxic stress.

      Keywords

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