title: Gender-related penetrance and de novo GTP-cyclohydrolase I gene mutations in dopa-responsive dystonia.
abstract: We evaluated the influence of gender on penetrance of GTP-cyclohydrolase I (GCH) gene mutations in hereditary progressive dystonia/dopa-responsive dystonia (HPD/DRD) and determined whether some apparently sporadic HPD/DRD patients owe their disorder to a de novo mutation of the GCH gene. Previous clinical investigations of HPD/DRD have shown a predominance of affected women, with approximately half of HPD/DRD patients being sporadic. We conducted genomic DNA sequencing of the GCH gene in five HPD/DRD families having at least two generations of affected members and in four apparently sporadic cases and all of their parents. In the nine HPD/DRD pedigrees, we found independent mutations of the GCH gene (five deletions, one insertion, one nonsense mutation, and two point mutations at splice acceptor sites). The female-to-male ratio of the HPD/DRD patients was 4.3 with the penetrance of GCH gene mutations in women being 2.3 times higher than that in men (87% versus 38%, p = 0.026). There was no significant difference in the penetrance between maternally and paternally transmitted offspring. All of the four sporadic cases had de novo mutations because none of their parents were carriers. The results demonstrate gender-related incomplete penetrance of GCH gene mutations in HPD/DRD and suggest that this may not be due to genomic imprinting. Our data also suggest a relatively high spontaneous mutation rate of the GCH gene in this autosomal dominant disorder.
authors.affiliation: Human Neurochemical Pathology Laboratory, Clarke Institute of Psychiatry, Toronto, Ontario, Canada.
authors.forename: Y
authors.initials: Y
authors.lastname: Furukawa
authors.forename: A E
authors.initials: AE
authors.lastname: Lang
authors.forename: J M
authors.initials: JM
authors.lastname: Trugman
authors.forename: T D
authors.initials: TD
authors.lastname: Bird
authors.forename: A
authors.initials: A
authors.lastname: Hunter
authors.forename: M
authors.initials: M
authors.lastname: Sadeh
authors.forename: T
authors.initials: T
authors.lastname: Tagawa
authors.forename: P H
authors.initials: PH
authors.lastname: St George-Hyslop
authors.forename: M
authors.initials: M
authors.lastname: Guttman
authors.forename: L W
authors.initials: LW
authors.lastname: Morris
authors.forename: O
authors.initials: O
authors.lastname: Hornykiewicz
authors.forename: M
authors.initials: M
authors.lastname: Shimadzu
authors.forename: S J
authors.initials: SJ
authors.lastname: Kish
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D004252:DNA Mutational Analysis; D015259:Dopamine Agents / Q000627:therapeutic use; D004421:Dystonia / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005192:Family Health; D005260:Female; D006136:GTP Cyclohydrolase / Q000235:genetics*; D005799:Genes, Dominant; D006801:Humans; D007438:Introns / Q000235:genetics; D007980:Levodopa / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D019683:Penetrance; D017354:Point Mutation; D012737:Sex Factors
chemical_list: D015259:Dopamine Agents; D007980:Levodopa; D006136:GTP Cyclohydrolase