GCH1

The GCH1 gene provides instructions for making an enzyme called GTP cyclohydrolase. This enzyme is responsible for the first of three steps in the production of a molecule called tetrahydrobiopterin (BH4). Other enzymes carry out the second and third steps in this process.

Tetrahydrobiopterin plays a critical role in processing several protein building blocks (amino acids) in the body. For example, it works with the enzyme phenylalanine hydroxylase to convert an amino acid called phenylalanine into another amino acid, tyrosine. Tetrahydrobiopterin is also involved in reactions that produce chemicals in the brain called neurotransmitters, which transmit signals between nerve cells. Because it helps enzymes carry out chemical reactions, tetrahydrobiopterin is known as a cofactor.

tetrahydrobiopterin deficiency - caused by mutations in the GCH1 gene

When GCH1 mutations underlie tetrahydrobiopterin deficiency, the condition is known as GTP cyclohydrolase 1 (GTPCH) deficiency. At least six mutations that cause this disorder have been identified in the GCH1 gene. These mutations occur in both copies of the gene in each cell, and most change single amino acids in GTP cyclohydrolase.

Mutations in the GCH1 gene greatly reduce or eliminate the activity of GTP cyclohydrolase. Without enough of this enzyme, little or no tetrahydrobiopterin is produced. As a result, this cofactor is not available to participate in chemical reactions such as the conversion of phenylalanine to tyrosine. If phenylalanine from the diet is not converted to tyrosine, it can build up to toxic levels in the blood and other tissues. Nerve cells in the brain are particularly sensitive to phenylalanine levels, which is why excessive amounts of this substance can cause brain damage.

Additionally, a reduction in GTP cyclohydrolase activity disrupts the production of certain neurotransmitters in the brain. Because neurotransmitters are necessary for normal brain function, changes in the levels of these brain chemicals contribute to mental impairment in people with tetrahydrobiopterin deficiency.

other disorders - caused by mutations in the GCH1 gene

Low levels of GTP cyclohydrolase activity also cause a disorder called dopa-responsive dystonia, which is also known as Segawa syndrome or hereditary progressive dystonia with marked diurnal fluctuation. Dopa-responsive dystonia is characterized by progressive problems with movement beginning in childhood. Symptoms typically begin in the legs, causing muscle cramping and progressive difficulty with walking. Movement abnormalities are often worse late in the day or after exercise. When dopa-responsive dystonia appears later in life, its signs and symptoms often resemble those of Parkinson disease.

More than 90 mutations in the GCH1 gene have been identified in patients with this condition. These mutations occur in one copy of the gene in each cell. The mutations responsible for dopa-responsive dystonia result in an abnormal version of GTP cyclohydrolase that cannot play its role in tetrahydrobiopterin production. Researchers believe that the abnormal enzyme may also interfere with the activity of the normal version of GTP cyclohydrolase. As a result, the body makes less tetrahydrobiopterin than usual, which disrupts the production of an important neurotransmitter called dopamine. A shortage of dopamine in certain parts of the brain underlies the movement abnormalities characteristic of dopa-responsive dystonia.