The three-nucleotide deletion, ▵GAG (within the gene TOR1A), is the only proven cause of childhood-onset dystonia (DYT1). A potentially pathogenic role of additional sequence changes within TOR1A has not been conclusively shown.Methods:
DNA sequencing of exon 5 of TOR1A in a patient with DYT1.Results:
Detection of sequence change c.863G>A in exon 5 of TOR1A in the patient. The G>A transition results in an exchange of an arginine for glutamine (p.Arg288Gln) in subdomain α5 of TOR1A. Several findings point to a potentially pathogenic role of the sequence change in the patient: The base change is absent in 1000 control chromosomes; an Arg at position 288 of TOR1A has been conserved throughout vertebrate evolution, indicating an important role of Arg288 in TOR1A function; functional studies demonstrate enlarged perinuclear space in HEK293 cells overexpressing TOR1A with the p.Arg288Gln mutation. The same morphological changes are observed in cells overexpressing the common ▵GAG TOR1A mutation but not in cells overexpressing wild-type TOR1A.Conclusions:
The sequence change described here may be a novel pathogenic mutation of TOR1A in DYT1.