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Brain. 2017 Nov 1;140(11):2851-2859. doi: 10.1093/brain/awx230.

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

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Kariminejad-Najmabadi Pathology and Genetics Center, Tehran, Iran.
Department of Pathology, University of Gothenburg, Sahlgrenska University Hospital, Sweden.
Centre for Medical Research, The University of Western Australia and the Harry Perkins Institute for Medical Research, Nedlands, Western Australia, Australia.
Department of Radiology, Mahdieh Hospital, Shahid Beheshti University of Medical Science, Tehran, Iran.
Department of Diagnostic Genomics, Pathwest, QEII Medical Centre, Nedlands, Western Australia, Australia.
School of Health and Education, Division Biomedicine and Public Health, University of Skovde, SE-541 28, Skovde, Sweden.


See Ginevrino and Valente (doi:10.1093/brain/awx260) for a scientific commentary on this article. Autosomal dominant torsion dystonia-1 is a disease with incomplete penetrance most often caused by an in-frame GAG deletion (p.Glu303del) in the endoplasmic reticulum luminal protein torsinA encoded by TOR1A. We report an association of the homozygous dominant disease-causing TOR1A p.Glu303del mutation, and a novel homozygous missense variant (p.Gly318Ser) with a severe arthrogryposis phenotype with developmental delay, strabismus and tremor in three unrelated Iranian families. All parents who were carriers of the TOR1A variant showed no evidence of neurological symptoms or signs, indicating decreased penetrance similar to families with autosomal dominant torsion dystonia-1. The results from cell assays demonstrate that the p.Gly318Ser substitution causes a redistribution of torsinA from the endoplasmic reticulum to the nuclear envelope, similar to the hallmark of the p.Glu303del mutation. Our study highlights that TOR1A mutations should be considered in patients with severe arthrogryposis and further expands the phenotypic spectrum associated with TOR1A mutations.


DYT1 dystonia; TOR1A; TOR1A p.Glu303del; endoplasmic reticulum luminal protein torsinA; severe arthrogryposis


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