Novel Mutations in the Guanosine Triphosphate Cyclohydrolase 1 Gene Associated With DYT5 Dystonia

Abstract

To better understand the relationship between mutation of the guanosine triphosphate cyclohydrolase I (GCH1) gene and the etiology of DYT5 dystonia and to accumulate data on the mutation in the Japanese population for genetic diagnosis of the disease. Setting: Japanese population. Patients: Eight Japanese patients with suspected DYT5 dystonia were analyzed. Intervention: Direct genomic sequencing of 6 exons of GCH1 was performed. Main Outcome Measures: For patients who did not exhibit any abnormality in the sequence analysis, the possibility of exon deletions was examined. In cases for which cerebrospinal fluid was available, the concentrations of neopterin and biopterin were measured as an index of GCH1 enzyme activity. Results: In 2 patients, we found a new T106I mutation in exon 1 of GCH1, a position involved in the helix-turn-helix structure of the enzyme. In the third patient, we found a new mutation (a 15-base pair nucleotide deletion) in exon 5 that may cause a frameshift involving the active site. In the fourth patient, we detected a known nucleotide GϾA substitution in the splice site of intron 5, which has been reported to produce exon 5-skipped messenger RNA. The concentrations of both neopterin and biopterin in the cerebrospinal fluid of the third and fourth patients were markedly lower than the normal range, indicating that the GCH1 enzyme was functionally abnormal in these mutations. Gene dosage analysis showed that the fifth patient had a deletion of both exon 3 and exon 4, whereas the sixth patient had a deletion of exon 3. Conclusions: We found several novel, as well as known, GCH1 mutations in Japanese patients with DYT5 dystonia. In some of them, the GCH1 enzyme activity was proved to be impaired.

Four novel mutations in the GCH1 gene of Chinese patients with dopa‐responsive dystonia

“…Since 1994, more than 100 mutations of the GCH1 gene have been reported in DRD patients from different ethnic populations 6, 23. Although it is a very interesting topic, the reason why the GCH1 gene has so many different mutations in its coding region (including the splice sites) is yet to be explained.…”

Urinary Neopterin and Phenylalanine Loading Test as Tools for the Biochemical Diagnosis of Segawa Disease

“…p.K224R has been so far reported in three pedigrees associated with athetoid cerebral palsy (family Hu in Bandmann et al 1998), myoclonic dystonia (Leuzzi et al 2002) and adult-onset gait dystonia, rigidity and bradykinesia (Patient D97 in Garavaglia et al 2004). Since the first report (Furukawa et al 2000), few pedigrees harbouring gross deletion of the GCH1 gene have been reported (Klein et al 2002;Hagenah et al 2005;Ohta et al 2006;Clot et al 2009). Their phenotype overlaps with that of patients with less severe alterations.…”

Segawa syndrome due to mutation Q89X in the GCH1 gene: a possible founder effect in Córdoba (southern Spain)

“…There are a few reports of GCH1 mutations detected in two families in the same geographical region in Germany [22], France [23] and Italy [24]. Two apparently unrelated patients with a new mutation have recently been described in Japan [16] suggesting a common origin of the mutated chromosomes. Both Tassin et al and Uncini et al detected a common haplotype for four microsatellite markers in the GCH1 region which segregated with the respective mutation found in the French and Italian families.…”

“…This number of carriers of the mutation was much higher than expected, given a worldwide estimated prevalence of 0.5 per million for DRD [13], although this may be underestimated owing to underdiagnosis. Furthermore, most mutations in GCH1 are private [16]. Consequently, the finding of the same mutation in family members from two pedigrees with DYT5 dystonia who were originally thought to be unrelated prompted us to consider the possibility that our cohort may have descended from a single founder.…”