Mice lacking Cldn16 develop hypercalciuria and hypomagnesemia, which is similar to the phenotype of patients with familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) that carry pathogenic variants in CLDN1650. Here, CLDN16 is linked to familial primary hypomagnesemia with hypercalciuria and nephrocalcinosis.