GCH1 gene

More than 140 mutations in the GCH1 gene have been found to cause dopa-responsive dystonia. This condition is characterized by a pattern of involuntary muscle contractions (dystonia), tremors, and other uncontrolled movements and usually responds to treatment with a medication called L-Dopa. Dopa-responsive dystonia results when one copy of the GCH1 gene is mutated in each cell. Most GCH1 gene mutations that cause this condition change single amino acids in the GTP cyclohydrolase 1 enzyme. Researchers believe that the abnormal enzyme may interfere with the activity of the normal version of GTP cyclohydrolase 1 that is produced from the copy of the gene with no mutation. As a result, the amount of working enzyme in affected individuals is reduced by 80 percent or more. A reduction in functional GTP cyclohydrolase 1 enzyme causes less dopamine and serotonin to be produced, leading to the movement problems and other characteristic features of dopa-responsive dystonia.

At least seven mutations in the GCH1 gene have been found to cause tetrahydrobiopterin deficiency. When this condition is caused by GCH1 gene mutations, it is known as GTP cyclohydrolase 1 (GTPCH1) deficiency. GTPCH1 deficiency accounts for about 4 percent of all cases of tetrahydrobiopterin deficiency.

GTPCH1 deficiency results when two copies of the GCH1 gene are mutated in each cell. Most of the mutations responsible for this condition change single amino acids in GTP cyclohydrolase 1. These mutations greatly reduce or eliminate the activity of this enzyme. Without enough GTP cyclohydrolase 1, 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 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 1 activity disrupts the production of certain neurotransmitters in the brain. Because neurotransmitters are necessary for normal brain function, changes in the levels of these chemicals contribute to intellectual disability in people with GTPCH1 deficiency.

Tetrahydrobiopterin deficiency is more severe than dopa-responsive dystonia likely because both copies of the GCH1 gene are mutated, which leads to a more severe enzyme shortage than in dopa-responsive dystonia, in which only one copy of the gene has a mutation.