A homozygous p.(Arg371Ser) mutation in FICD de-regulates AMPylation of the human endoplasmic reticulum chaperone BiP causing infancy-onset diabetes and severe neurodevelopmental delay

Dysfunction of the endoplasmic reticulum (ER) in insulin-producing beta cells results in cell loss and diabetes mellitus. Here we report on 5 individuals from three different consanguineous families with infancy-onset diabetes mellitus and severe neurodevelopmental delay caused by a homozygous p.(Arg371Ser) mutation in FICD . The FICD gene encodes a bifunctional Fic domain-containing enzyme that regulates the ER Hsp70 chaperone, BiP, via catalysis of two antagonistic reactions: inhibitory AMPylation and stimulatory deAMPylation of BiP. Arg371 is a conserved residue in the Fic domain active site. The FICDR371S mutation partially compromises BiP AMPylation in vitro but eliminates all detectable deAMPylation activity. Overexpression of FICDR371S or knock-in of the mutation at the FICD locus of stressed CHO cells result in inappropriately elevated levels of AMPylated BiP. These findings, guided by human genetics, highlight the destructive consequences of de-regulated BiP AMPylation and raise the prospect of tuning FICD’s antagonistic activities towards therapeutic ends. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement Supported by: Wellcome Trust Principal Research Fellowship to D.R. (Wellcome 200848/Z/16/Z). A Diabetes UK RD Lawrence fellowship to E.D.F. (Grant number 19_0005971) A Wellcome Trust Senior Research Fellowship to S.E.F. (105636/Z/14/Z). M.N.W. is in receipt of an Independent Fellowship from the Exeter Diabetes Centre of Excellence funded by Research Englands Expanding Excellence in England (E3) fund. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee/IRB of University of Exeter, Exeter, United Kingdom gave ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors