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GTP‐cyclohydrolase I gene mutations in patients with autosomal dominant and recessive GTP‐CH1 deficiency: Identification and functional characterization of four novel mutations
Author(s) -
Garavaglia B.,
Invernizzi F.,
Carbone M. L. Agostoni,
Viscardi V.,
Saracino F.,
Ghezzi D.,
Zeviani M.,
Zorzi G.,
Nardocci N.
Publication year - 2004
Publication title -
journal of inherited metabolic disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 102
eISSN - 1573-2665
pISSN - 0141-8955
DOI - 10.1023/b:boli.0000037349.08483.96
Subject(s) - missense mutation , frameshift mutation , complementation , genetics , mutation , gtp cyclohydrolase i , biology , gene , gtp' , gene mutation , compound heterozygosity , microbiology and biotechnology , phenotype , biochemistry , enzyme , tetrahydrobiopterin , cofactor
Summary: GTP‐cyclohydrolase I (GTP‐CH1, EC 3.5.4.16) is encoded by the GCH1 gene. Mutations in the GCH1 gene cause both dopa‐responsive dystonia (McKusick 128230) and recessive GTP‐CH1 deficiency (McKusick 600225). The exact molecular mechanism resulting in decreased GTP‐CH1 activity in the patients is still obscure. We report the clinical features and molecular and functional study of the GCH1 gene in eight Italian patients affected by dominant and recessive GTP‐CH1 deficiency. All the studied patients had mutations in the GCH1 gene. Three missense mutations (V205G, K224R, P199A), a frameshift mutation (ΔG693), and a splice‐site mutation (ivs5 + 1g > c) were found. Except for K224R these are all novel mutations. To analyse the defect caused by the novel mutations, an in vivo functional assay in a Saccharomyces cerevisiae strain lacking the endogenous gene encoding GTP‐CH1 ( FOL2 ) was performed. Complementation analysis showed that the ΔG693 and V205G mutations abolish the enzymatic function, while the P199A mutation causes a conditional defect. In conclusion, the clinical phenotypes displayed by our patients confirm the wide clinical spectrum of the disease and further support the lack of correlation between a given mutation and a clinical phenotype. Complementation analysis in yeast is a useful tool for confirming the pathogenetic effect of GCH1 mutations.