A common point mutation in the tyrosine hydroxylase gene in autosomal recessive L-DOPA-responsive dystonia in the Dutch population

Abstract

This report concerns one new mutation in the tyrosine hydroxylase (TH) gene in three patients originating from three unrelated Dutch families with autosomal recessive L-DOPA-responsive dystonia (DRD). In this study, all exons of the TH gene were amplified by the polymerase chain reaction and subjected to analyses by single-strand conformation polymorphism. An aberrant migration pattern was observed for exon 6 of the TH gene in all patients. Direct sequencing of the coding region of exon 6 revealed the presence of one novel missense mutation. An a698g transition resulted in the substitution of the evolutionary conserved arginine 233 by a histidine (R233H). All patients were homozygous for the mutation. This new mutation in the TH gene was confirmed by restriction enzyme analysis with the restriction enzyme HhaI. Thus, a high proportion of defective TH alleles may be R233H in The Netherlands.

Effect of torsinA on membrane proteins reveals a loss of function and a dominant-negative phenotype of the dystonia-associated ΔE-torsinA mutant

“…For instance, mutations in two important genes in the biosynthesis of dopamine; the GTP cyclohydrolase (8)(9)(10) and tyrosine hydroxylase genes (11)(12), were found in patients with doparesponsive dystonia. Similarly, a mutation in the dopamine D2 receptor (D2DAR) was associated with myoclonus dystonia (13).…”

A branch site mutation leading to aberrant splicing of the human tyrosine hydroxylase gene in a child with a severe extrapyramidal movement disorder

“…Eight missense mutations and one deletion in the TH gene resulting in reduced TH activity are known (Lu$ decke et al 1996 ;Lu$ decke et al 1995 ;Knappskog et al 1995 ;Van den Heuvel et al 1998 ;Bra$ utigam et al 1999 ;Wevers et al 1999 ;Swaans et al 2000). Here we report the identification of a branch site mutation in the human TH gene.…”

“…TH deficiency has been described clinically as Segawa's syndrome , -dopa-responsive parkinsonism in infancy (Lu$ decke et al 1996) or as -dopa-responsive dystonia (Knappskog et al 1995 ;Van den Heuvel et al 1998).…”

“…They are therefore heterozygous for the 698G A mutation ( Fig. 1) (Van den Heuvel et al 1998). This mutation was confirmed by DNA sequence analysis (data not shown).…”

“…The described patient followed an especially severe clinical course and was found to be a compound heterozygote. On the other allele the 698G A transition in exon 6 (numbering according to hTH type 4 cDNA described by Nagatsu & Ichinose 1991) is present (Van den Heuvel et al 1998).…”