McCune-Albright syndrome

At least three GNAS gene mutations have been identified in people with McCune-Albright syndrome, a disorder that affects the bones, skin, and several hormone-producing (endocrine) tissues. These mutations result in an abnormal version of the G protein that causes the adenylate cyclase enzyme to be constantly turned on (constitutively activated). Constitutive activation of the adenylate cyclase enzyme leads to over-production of several hormones, resulting in the signs and symptoms of McCune-Albright syndrome.

McCune-Albright syndrome is not inherited. The gene mutation that causes this disorder is described as somatic. Instead of being passed from parent to child, somatic mutations are acquired during a person's lifetime and are present only in certain cells. McCune-Albright syndrome is caused by a random mutation in the GNAS gene that occurs very early in development. As a result, some of the body's cells have a normal version of the GNAS gene, while other cells have the mutated version. This phenomenon is called mosaicism. The severity of this disorder and its specific features depend on the number and location of cells that have the mutated GNAS gene.

Primary macronodular adrenal hyperplasia

At least two mutations in the GNAS gene have been identified in people with primary macronodular adrenal hyperplasia (PMAH), a disorder that causes multiple lumps (nodules) to form in the adrenal glands, which are small hormone-producing glands located on top of each kidney. These nodules cause adrenal gland enlargement (hyperplasia) and result in production of higher-than-normal levels of the hormone cortisol. Cortisol normally helps maintain blood glucose levels, protects the body from physical stress, and suppresses inflammation. Increased cortisol levels can lead to weight gain in the face and upper body, fragile skin, bone loss, fatigue, and other health problems, which often occur in people with PMAH.

The GNAS gene mutations that cause PMAH are believed to result in an overactive G protein. Research suggests that the overactive G protein may increase levels of adenylate cyclase, which results in the overproduction of another compound called cyclic AMP (cAMP). An excess of cAMP may trigger abnormal cell growth and lead to the adrenal nodules characteristic of PMAH.

As in McCune-Albright syndrome, the GNAS gene mutations that cause PMAH are somatic mutations that are believed to occur early in embryonic development. Cells with the mutated GNAS gene can be found in both adrenal glands.

Progressive osseous heteroplasia

At least 14 GNAS gene mutations have been identified in people with progressive osseous heteroplasia. People normally inherit one copy of each gene from their mother and one copy from their father. For most genes, both copies are active, or "turned on," in all cells. For a small subset of genes, however, only one of the two gene copies is active. For some of these genes, only the copy inherited from a person's father (the paternal copy) is active, while for other genes, only the copy inherited from a person's mother (the maternal copy) is active. These differences in gene activation based on the gene's parent of origin are caused by a phenomenon called genomic imprinting.

The GNAS gene has a complex genomic imprinting pattern. In some parts of the body the maternal copy of the gene is active, while in others the paternal copy is active. Progressive osseous heteroplasia is caused by certain mutations that affect the paternal copy of the gene. These mutations disrupt the function of the G protein and impair its ability to regulate osteogenesis. Impaired regulation of osteogenesis results in the ectopic production of bony tissue in the skin and muscles seen in progressive osseous heteroplasia.

Cholangiocarcinoma

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Other disorders

Mutations in the GNAS gene also cause Albright hereditary osteodystrophy (AHO), which is characterized by short stature, obesity, unusually short fingers and toes (brachydactyly), ectopic development of bony tissue under the skin, and other skeletal abnormalities. When a mutation that causes AHO is inherited from a person's mother, the affected individual will usually have AHO accompanied by a resistance to multiple hormones (a condition called pseudohypoparathyroidism type Ia, or PHPIa). A paternally-inherited mutation can result in AHO without endocrine problems; this form of the condition is called pseudopseudohypoparathyroidism (PPHP).

Somatic mutations in the GNAS gene have been found in tumors of the endocrine glands and in fibrous lesions (dysplasia) that can occur in bones. These mutations are believed to result in an overactive G protein, which triggers abnormal cell growth. Because the cells with mutations are not as widespread in the body as in McCune-Albright syndrome (described above), the abnormal growth is confined to a particular gland or fibrous lesion.