S. Ueno et M. Hirano, Missense mutants inactivate guanosine triphosphate cyclohydrolase I in hereditary progressive dystonia, BRAIN DEVEL, 2000, pp. S111-S114
Hereditary progressive dystonia (HPD) with marked diurnal fluctuation is ca
used by mutant guanosine triphosphate (GTP) cyclohydrolase I (GCH). The cli
nical presentation of dominant HPD varies considerably. We proposed the hyp
othesis that a relative increase of mutant GCH capable of inhibiting normal
GCH is responsible for heterogeneous phenotypic manifestations. In a Japan
ese family with a novel G90V mutation, an affected heterozygote had a highe
r mutant/normal mRNA ratio than an unaffected heterozygote. Co-expression a
nalysis showed that mutant enzyme (GCH-G90V) inactivated the normal enzyme
in the COS cells. Similarly, GCH-G203R showed the dominant negative effects
. These results supported our proposed hypothesis. (C) 2000 Elsevier Scienc
e B.V. All lights reserved.