GNA11 gene

At least five mutations in the GNA11 gene have been found in individuals with autosomal dominant hypocalcemia type 2. This condition is characterized by low levels of calcium in the blood (hypocalcemia). The mutations involved in this condition change single protein building blocks (amino acids) in Gα₁₁. These genetic changes are called activating mutations because the altered alpha subunit is overactive, sending signals to block a rise in calcium levels, even when levels are very low. As a result, calcium levels in the blood remain abnormally low, causing hypocalcemia. Hypocalcemia can cause muscle cramping and seizures, although about half of people with the condition have no associated health problems.

Because overactive Gα₁₁ signaling blocks the production of parathyroid hormone, the levels of this hormone in the blood can be abnormally low, which is known as hypoparathyroidism. For this reason, autosomal dominant hypocalcemia is sometimes referred to as autosomal dominant hypoparathyroidism.

Germline mutations in the GNA11 gene are also involved in a different condition related to abnormal calcium concentrations. Genetic changes that impair Gα₁₁ signaling cause familial hypocalciuric hypercalcemia type 2. In contrast to autosomal dominant hypocalcemia (described above), this condition is characterized by high levels of calcium in the blood (hypercalcemia) and low levels of calcium in the urine (hypocalciuria). Because Gα₁₁ signaling to block parathyroid hormone release is impaired, calcium levels in the blood rise, leading to hypercalcemia. Affected individuals typically have no symptoms related to the condition.

The gene mutations that cause autosomal dominant hypocalcemia (described above) are typically inherited and found in every cell in the body (known as germline mutations). However, some gene mutations are not inherited and are instead acquired during a person's lifetime. These changes, which are called somatic mutations, are present only in certain cells. Somatic mutations in the GNA11 gene have been found in cancerous tumors in the eye known as uveal melanomas. These tumors occur in the colored part of the eye (the iris) or in related tissues known as the ciliary body and the choroid (collectively, these tissues are called the uvea). 

Less commonly, GNA11 gene mutations are associated with a type of skin tumor called a blue nevus, so named because of its characteristic bluish appearance. This type of growth is typically noncancerous. GNA11 gene mutations are activating, leading to production of an overactive Gα₁₁ protein that stimulates uncontrolled proliferation of the pigment-producing cells (melanocytes) in the uvea or in the skin.

Individuals with uveal melanomas or blue nevi appear to have normal levels of calcium in their blood, and people with an inherited GNA11-related calcium concentration disorder do not seem to have an increased risk of developing one of these types of tumors.