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A splice mutation in the GTP cyclohydrolase I gene causes dopa‐responsive dystonia by exon skipping
Author(s) -
Skrygan M.,
Bartholomé B.,
Bonafé L.,
Blau N.,
Bartholomé K.
Publication year - 2001
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/a:1010544316387
Subject(s) - exon , gtp cyclohydrolase i , exon skipping , splice , genetics , mutation , dystonia , gene , human genetics , splice site mutation , rna splicing , medicine , biology , alternative splicing , endocrinology , neuroscience , rna , nitric oxide synthase , nitric oxide , tetrahydrobiopterin
Four different mutations in the GTP cyclohydrolase I gene were found (P199L, M211V, IVS5+1G>A, G203R) in 6 out of 33 families with dopa‐responsive dystonia. A splice mutation (IVS5+1G>A) located at the border of exon 5 to intron 5 was found in one of these families. Three members of the family carry the IVS5+1G>A mutation on one allele, inherited from the father to the daughter and son. Examination of the mRNA showed an exon 5 skipping that results in a reduction of enzyme activity in cultured fibroblasts to 4–17% compared to controls. The father and daughter never had clinical symptoms of dopa‐responsive dystonia. The son was symptomatic at the age of 3 years and was treated successfully with L‐dopa/carbidopa. After 20 years this therapy was terminated and for the next 6 years he was free of symptoms. With increased motoric activity, symptoms reappeared and the therapy was reintroduced.