title: Novel mutations in the guanosine triphosphate cyclohydrolase 1 gene associated with DYT5 dystonia.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  Japanese population. Patients Eight Japanese patients with suspected DYT5 dystonia were analyzed. Intervention Direct genomic sequencing of 6 exons of GCH1 was performed.
  
  
  METHODS
  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 G>A 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.
authors.affiliation: Division of Clinical Immunology, Graduate School of Medical Sciences, Kitasato University, Department of Neurology, National Sagamihara Hospital, Sagamihara, Kanagawa, Japan.
authors.forename: Etsuro
authors.initials: E
authors.lastname: Ohta
authors.forename: Manabu
authors.initials: M
authors.lastname: Funayama
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ichinose
authors.forename: Itaru
authors.initials: I
authors.lastname: Toyoshima
authors.forename: Fumi
authors.initials: F
authors.lastname: Urano
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Matsuo
authors.forename: Nishida
authors.initials: N
authors.lastname: Tomoko
authors.forename: Konishi
authors.initials: K
authors.lastname: Yukihiko
authors.forename: Syuji
authors.initials: S
authors.lastname: Yoshino
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yokoyama
authors.forename: Hideki
authors.initials: H
authors.lastname: Shimazu
authors.forename: Koji
authors.initials: K
authors.lastname: Maeda
authors.forename: Kazuko
authors.initials: K
authors.lastname: Hasegawa
authors.forename: Fumiya
authors.initials: F
authors.lastname: Obata
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D001708:Biopterins / Q000134:cerebrospinal fluid; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis / Q000379:methods; D020821:Dystonic Disorders / Q000134:cerebrospinal fluid / Q000235:genetics* / Q000378:metabolism; D005091:Exons; D005260:Female; D006136:GTP Cyclohydrolase / Q000235:genetics*; D006801:Humans; D007532:Isoleucine / Q000235:genetics; D007564:Japan; D008297:Male; D018895:Microsatellite Repeats; D009154:Mutation; D019798:Neopterin / Q000134:cerebrospinal fluid; D013912:Threonine / Q000235:genetics
chemical_list: D007532:Isoleucine; D001708:Biopterins; D013912:Threonine; D019798:Neopterin; D006136:GTP Cyclohydrolase