The intracellular localization and the ionic permeation of TRPV6 triggers chronic pancreatitis, skeletal dysplasia and is connected to mucolipidosis type II.

Heterozygous TRPV6 mutations, which reduce significantly the Ca2+-permeability of the channel, lead to chronic pancreatitis and, if both TRPV6-alleles are affected, to skeletal dysplasia with neonatal transient hyperparathyroidism (TNHP) of newborns. We show that TRPV6 channels are localized in intracellular vesicles in pancreatic acinar cells, in the syncytiotrophoblast layer of the placenta and, after overexpression, in HEK293 cells. We identify three motifs within the TRPV6 sequence a N-glycosylation site, an ER- and a sorting-motif which in concerted action leads to an intracellular localisation. The transport to vesicles depends on the N-glycosylation site of TRPV6. We found that the channel interacts with the cation independent mannose-6-phosphate receptor (CI-M6PR/IGF2R) indicating that TRPV6 is a target of the GNPTAB enzyme which targets proteins for endosomes/lysosomes by generating a mannose-6-phosphate residue at the N-glycosyl site chain of TRPV6. Defects in the GNTPAB enzyme cause mucolipidosis type II and patients show at the time of birth overlapping defects with patients with TRPV6 mutations. We show that a TRPV6 mutation, I223T, frequently found in patients with pancreatitis/skeletal dysplasia sticks to the ER but shows not reduced channel activity. The I223T mutation causes the diseases because the TRPV6 channel is not transferred to intracellular vesicles.