Novel TOR1A mutation p.Arg288Gln in early-onset dystonia (DYT1).
BACKGROUND
The three-nucleotide deletion, triangle upGAG (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 alpha5 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 triangle upGAG 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.
Zirn
B
B
Institute of Human Genetics, Schlangenzahl 14, D-35392 Giessen, Germany.
Grundmann
K
K
Huppke
P
P
Puthenparampil
J
J
Wolburg
H
H
Riess
O
O
Müller
U
U
D000293:Adolescent; D000595:Amino Acid Sequence; D002467:Cell Nucleus / Q000378:metabolism; D003680:Deglutition Disorders / Q000175:diagnosis / Q000235:genetics; D018450:Disease Progression; D020821:Dystonic Disorders / Q000175:diagnosis* / Q000235:genetics*; D005091:Exons; D005260:Female; D006801:Humans; D008854:Microscopy, Electron; D018832:Molecular Chaperones / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D017422:Sequence Analysis, DNA; D017386:Sequence Homology, Amino Acid
D018832:Molecular Chaperones; C108175:TOR1A protein, human