Infancy‐onset diabetes caused by de‐regulated <scp>AMPylation</scp> of the human endoplasmic reticulum chaperone <scp>BiP</scp>

<jats:title>Abstract</jats:title><jats:p>Dysfunction of the endoplasmic reticulum (ER) in insulin‐producing beta cells results in cell loss and diabetes mellitus. Here we report on five individuals from three different consanguineous families with infancy‐onset diabetes mellitus and severe neurodevelopmental delay caused by a homozygous p.(Arg371Ser) mutation in <jats:italic>FICD</jats:italic>. The <jats:italic>FICD</jats:italic> 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 FICD<jats:sup>R371S</jats:sup> mutation partially compromises BiP AMPylation <jats:italic>in vitro</jats:italic> but eliminates all detectable deAMPylation activity. Overexpression of FICD<jats:sup>R371S</jats:sup> or knock‐in of the mutation at the <jats:italic>FICD</jats:italic> locus of stressed CHO cells results in inappropriately elevated levels of AMPylated BiP and compromised secretion. 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.</jats:p>