Glial Cells Missing-2 (GCM2) Transactivates the Calcium-Sensing Receptor Gene: Effect of a Dominant-Negative GCM2 Mutant Associated With Autosomal Dominant Hypoparathyroidism

Glial cells missing-2 (GCM2) is a transcription factor expressed in the parathyroid hormone (PTH), secreting cells of the parathyroid gland and is essential for their development. Thus far, downstream targets of GCM2 have not been identified. Here, we show that both promoters (P1 and P2) of the calcium,sensing receptor (CASR) gene, a differentiation marker for the parathyroid gland, are transactivated by wild,type GCM2. GCM response elements within CASR P1 (-451 to -441; relative to the transcription start site at + 1) and CASR P2 (-166 to -156) were identified by mutated promoter-reporter studies as well as oligonucleotide precipitation assays. Primary hypoparathyroidism is a heterogeneous group of conditions characterized by hypocalcemia and hyperphosphatemia due to deficient PTH secretion. A few cases of familial isolated hypoparathyroidism with autosomal recessive inheritance have been identified that are caused by homozygous inactivating mutations in the GCM2 gene. We describe the GCM2 mutations in two families with hypoparathyroidism, one inherited in an autosomal recessive fashion and the other in an autosomal dominant manner. In transfection studies using a promoter-reporter construct having synthetic multimerized GCM elements in the promoter, the dominantly inherited mutant GCM2 exerted a dominant, negative effect on wild-type GCM2 activity, whereas recessively inherited mutants did not. In addition, we show that the transactivation of the CASR promoter-reporter constructs by wild-type GCM2 is completely abolished in the presence of the dominant-negative mutant GCM2.