A novel polymorphism at the GNAS1 gene associated with low circulating calcium levels.

The concentration of calcium in the extracellular fluid is crucial for several physiological functions in humans and in normal conditions its circulating levels are maintained between 8.5-10.5 mg/dl. Among the regulators of calcium homeostasis parathyroid hormone (PTH) acts though the G-protein coupled PTH receptor and a hormone-sensitive adenylate cyclase, with Gsα subunit (stimulatory guanine nucleotide-binding protein alpha-subunit) being responsible for the stimulation of the catalytic complex. Mutations of the Gsα encoding gene, GNAS1, are causal for some forms of congenital hypocalcemia. In the present study genetic variability in the GNAS1 gene was analyzed in a group of hypocalcemic patients collected through the Italian Register of Primary Hypoparathyroidism (RIIP). We identified a new intronic variant of the GNAS1 gene, consisting of a T>C polymorphism. This polymorphism was studied in a group of unrelated healthy subjects for a possible association with bone turnover biomarkers and bone mineral density. The T>C polymorphism was found in 18% of the studied populations, with 15% heterozygous TC and 3% homozygous CC (Pearson χ(2)analysis: p=0.04). A significant association with low serum calcium levels was found in healthy subjects carrying the T > C polymorphism (ANCOVA analysis: p=0.04). These results support segregation of a novel GNAS1 gene intronic variant with low calcium levels in primary hypoparathyroidism, pseudo-hypoparathyroidism and in the general population.