Mutations in GTP-cyclohydrolase I gene and vitiligo

Abstract

Sporadic and familial cases of vitiligo, some of them associated with autoimmune endocrine disorders, have been described. Although an autosomal dominant inheritance with low penetrance is suspected, no genetic locus has yet been identified. It has been shown that tetrahydrobiopterin regulates melanin biosynthesis, and that patients with vitiligo have abnormalities in this metabolic pathway. Tetrahydrobiopterin is an essential cofactor for three aromatic-acid mono-oxygenases—phenylalanine, tyrosine, and tryptophan hydrolases—being necessary not only for the synthesis of melanin (controlling tyrosine supply from phenylalanine) but also in the synthesis of catecholamines and serotonin. Because GTP-cyclohydrolase I (GTP-CH I) is the initial and rate-limiting enzyme in tetrahydrobiopterin synthesis, a decrease in its activity could cause vitiligo. I studied patients with dopa-responsive dystonia (DRD), a dominantly inherited disorder with reduced penetrance which is caused by mutations in the GTP-CH I gene. Clinically, DRD is characterised by dystonia and parkinsonism. Two families (seven in family A, and five in family B) were studied. There were four patients with DRD in family A, and two in family B. All patients met clinical criteria for DRD. DNA sequencing of the GTP-CH I gene showed a different missense mutation in each family. Base-pair changes were A532G533A534→A532G533C534 in family A, and C67C68C69→C67T68C69 in family B. These base-pair changes caused non-conservative aminoacid changes (Arg178Ser and Pro23Leu, respectively). While no member of family A without symptoms had the mutation, a carrier was identified in family B. Three of the four patients with DRD in family A also had vitiligo (figure). The only patient with DRD who did not have vitiligo in this family was a 16-year-old woman with mild dystonia. The other family members did not have vitiligo. In family B, only the most severely affected patient with DRD had vitiligo. Laboratory investigations ruled out known vitiligo-associated disorders. Activity of GTP-CH I in mononuclear blood cells from patients with DRD is less than 20% of normal. A similar decrease may be present in melanocytes of patients with DRD. Paradoxically, Schallreuter and colleagues reported that the activity of GTP-CH I was increased in vitiligo. These authors pointed to 4a-hydroxytetrahydrobiopterin dehydratase as the enzyme whose dysfunction could be responsible for vitiligo, and proposed that vitiligo could be due to the accumulation of 7-tetrahydrobiopterin, a potent competitive inhibitor of phenylalanine hydroxylase. Though both GTP-CH I and 4a-hydroxytetrahydrobiopterin dehydratase deficiencies can lead to diminished supply of tyrosine from phenylalanine, the presence of vitiligo in DRD suggests that the mechanisms proposed by Schallreuter and colleagues may not apply to all cases of vitiligo.