Mutations in GNAL cause primary torsion dystonia

Laurie Ozelius and colleagues identify mutations in GNAL in families with primary torsion dystonia, a movement disorder characterized by repetitive twisting muscle contractions and postures. GNAL encodes Gα olf , a stimulatory G protein α subunit. Dystonia is a movement disorder characterized by repetitive twisting muscle contractions and postures 1 , 2 . Its molecular pathophysiology is poorly understood, in part owing to limited knowledge of the genetic basis of the disorder. Only three genes for primary torsion dystonia (PTD), TOR1A (DYT1) 3 , THAP1 (DYT6) 4 and CIZ1 (ref. 5 ), have been identified. Using exome sequencing in two families with PTD, we identified a new causative gene, GNAL , with a nonsense mutation encoding p.Ser293* resulting in a premature stop codon in one family and a missense mutation encoding p.Val137Met in the other. Screening of GNAL in 39 families with PTD identified 6 additional new mutations in this gene. Impaired function of several of the mutants was shown by bioluminescence resonance energy transfer (BRET) assays.