New mutations behind heritable hypercalcemia and hypocalcemia identified

Image: PD G protein coupled receptor

1. Loss-of-function mutations in Gɑ₁₁ cause type 2 familial hypocalciuric hypercalcemia.

2.  Gain-of-function mutations in Gɑ₁₁ can cause autosomal dominant hypocalcemia

Study Rundown: The calcium-sensing receptor (CaSR) is expressed in two key regulators of calcium homeostasis: the parathyroid and the kidney. High levels of calcium activate CaSR, leading to inhibition of parathyroid hormone (PTH) release and reduced calcium reabsorption in the renal tubules. CaSR, in effect, determines the body’s calcium set point.

In type 1 familial hypocalciuric hypercalcemia, the body’s calcium set point is increased by loss-of-function mutations in CaSR. On the other hand, CaSR gain-of-function mutations lower the calcium set point. This is known as autosomal dominant hypocalcemia.

Since CaSR is a G-protein coupled receptor (GPCR), the authors hypothesized that inactivating and activating mutations in the coupled G-protein, Gɑ₁₁, could cause subtypes of FHH and autosomal dominant hypocalcemia, respectively.

Indeed, a Gɑ₁₁ loss-of-function mutation was found in a family with type 2 FHH and Gɑ₁₁ gain-of-function mutations were identified in 2 individuals with autosomal dominant hypocalcemia.

Click to read the study in the New England Journal of Medicine

Relevant Reading: Diseases associated with the extracellular calcium-sensing receptor

In-Depth [genetic study]: A 3-base pair deletion in the gene encoding Gɑ₁₁ was found to co-segregate with the disease in a family with type 2 FHH. A missense mutation in the gene was also identified in an unrelated individual with FHH. In vitro, these mutations were shown to reduce the sensitivity of cells to extracellular calcium, suggesting a loss of function in Gɑ₁₁. Protein modeling suggests that the mutations inhibit the enzyme’s ability to transition to its active state.

The authors were also able to find missense mutations in Gɑ₁₁ in two patients with hypocalcemia. In vitro studies showed that these mutations increased the sensitivity of cells to extracellular calcium – a gain of function. Protein modeling suggests that the mutations prolong the time Gɑ₁₁ spends in its active GTP-bound state.

This study provides convincing evidence for the role of Gɑ₁₁ in forms of hypercalcemia and hypocalcemia by combining genetic, in vitro and protein modeling data. However, Gɑ₁₁ mutations are not the final word on FHH or autosomal dominant hypocalcemia. Only 3 of the 18 unrelated patients tested had Gɑ₁₁ mutations. The mutations in the other 15 remain unknown.

By Tomi Jun and Mitalee Patil

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