TOR1A variants cause a severe arthrogryposis with developmental delay, strabismus and tremor

Introduction: Autosomal dominant torsion dystonia-1 is a disease withincomplete penetrance most often caused by an in-frame GAG deletion(p.Glu303del) in the endoplasmic reticulum luminal protein torsinA encodedby TOR1A.Methods: Wereport an association of the homozygous dominant diseasecausingTOR1Ap.Glu303del mutation, and a novel homozygous missensevariant (p.Gly318Ser) with a severe arthrogryposis phenotype withdevelopmental delay,strabismus and tremor in three unrelated families.Results: All parents who were carriers of the TOR1A variant showed noevidence of neurological symptoms or signs, indicating decreased penetrancesimilar to families with autosomal dominant torsion dystonia-1. The resultsfrom cell assays demonstrate that the p.Gly318Ser substitution causes aredistribution of torsinA from the endoplasmic reticulum to the nuclearenvelope, similar to the hallmark of the p.Glu303del mutation.Conclusion: Our study highlights that TOR1A mutations should be consideredin patients with severe arthrogryposis and further expands the phenotypicspectrum associated with TOR1A.

Keywords:

TOR1A , Endoplasmic reticulum luminal protein torsinA , DYT1 dystonia , TOR1Ap.Glu303del , Severe arthrogryposis