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Functional Studies of Tyrosine Hydroxylase Missense Variants Reveal Distinct Patterns of Molecular Defects in Dopa ‐Responsive Dystonia
Author(s) -
Fossbakk Agnete,
Kleppe Rune,
Knappskog Per M.,
Martinez Aurora,
Haavik Jan
Publication year - 2014
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22565
Subject(s) - missense mutation , tyrosine hydroxylase , biology , tyrosine , mutant , genetics , phenotype , phenylalanine hydroxylase , dystonia , endocrinology , phenylalanine , biochemistry , gene , enzyme , amino acid , neuroscience
ABSTRACT Congenital tyrosine hydroxylase deficiency ( THD ) is found in autosomal‐recessive Dopa ‐responsive dystonia and related neurological syndromes. The clinical manifestations of THD are variable, ranging from early‐onset lethal disease to mild P arkinson disease‐like symptoms appearing in adolescence. Until 2014, approximately 70 THD patients with a total of 40 different disease‐related missense mutations, five nonsense mutations, and three mutations in the promoter region of the tyrosine hydroxylase ( TH ) gene have been reported. We collected clinical and biochemical data in the literature for all variants, and also generated mutant forms of TH variants previously not studied ( N = 23). We compared the in vitro solubility, thermal stability, and kinetic properties of the TH variants to determine the cause(s) of their impaired enzyme activity, and found great heterogeneity in all these properties among the mutated forms. Some TH variants had specific kinetic anomalies and phenylalanine hydroxylase, and Dopa oxidase activities were measured for variants that showed signs of altered substrate binding. p. A rg233 H is, p. G ly247 S er, and p. P he375 L eu had shifted substrate specificity from tyrosine to phenylalanine and Dopa , whereas p. C ys359 P he had an impaired activity toward these substrates. The new data about pathogenic mechanisms presented are expected to contribute to develop individualized therapy for THD patients.