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 FICDs antagonistic activities towards therapeutic ends.