Uniting the divergent Wolfram syndrome-linked proteins WFS1 and CISD2 as modulators of Ca2+ signaling.

Mutations in WFS1 (which encodes Wolframin, WFS1) and CISD2 (which encodes CDGSH iron sulfur domain 2) result in Wolfram syndrome (WS), a rare genetic disorder that starts with juvenile diabetes and progresses to neurological dysfunction. WFS1 and CISD2 belong to different protein families with distinct properties. Despite differences between WFS1 and CISD2, loss-of-function mutations in these proteins result in similar disease phenotypes, suggesting that they have convergent roles. WFS1 and CISD2 both localize at the endoplasmic reticulum (ER), the main intracellular calcium (Ca2+) store, which is implicated in several diseases, including WS. Here, we not only review the roles of WFS1 and CISD2 in Ca2+ signaling modulation but also point out knowledge gaps. Because WFS1 and CISD2 form complexes with Ca2+ transporters and Ca2+ channels, it is thought that they influence the activity of these transport systems in cells. Together, the studies reviewed here provide a better understanding of the pathogenesis and the severe disease burden of WS and may contribute to the development of therapeutics.