Mutations in a single TRPV6 allele trigger chronic pancreatitis while loss of both alleles is responsible for skeletal dysplasia in newborns. The latter clinical presentation is accompanied by elevated serum levels of the parathyroid hormone, a condition known as transient neonatal hyperparathyroidism (TNHP). In humans, TRPV6 is abundantly expressed in the primary fetal-maternal interface in the placenta, as well as in pancreatic acini and within a few exocrine glands including salivary and lacrimal glands. However, inconsistent results regarding the cellular localization have complicated elucidation of the exact function within these tissues. We have verified an intracellular localization of TRPV6 within vesicles and identified a sorting motive, a glycosylation site and an ER-retention motive within the sequence, which together account for the observed channel localization. This is in contradiction to postulated functions of TRPV6 being responsible for calcium uptake into epithelial cells, which would require TRPV6 localization within the plasma membrane of expressing cells. We suggest that previous observations which demonstrate TRPV6 expression at the plasma membrane may result from overexpression and do not represent endogenous channel positioning. We showed that normal TRPV6 function requires the action of an enzyme (GNPTAB) and the subsequent interaction with a mannose-6-phosphate receptor to be delivered to endosomes. The GNPTAB enzyme marks proteins with mannose-6-phosphate and is known to be defective in patients suffering from mucolipidosis type II, which also present with skeletal dysplasia with elevated parathyroid hormone. The reliance of TRPV6 on this enzyme for correct localization and therefore function provides a possible explanation why patients suffering from either mucolipidosis type II or TRPV6 malfunction exhibit overlapping symptoms.

Ion channel, Mucolipidosis type II, Chronic pancreatitis, Skeletal dysplasia