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.

中文翻译：

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TOR1A变异会导致严重的关节软化症，并伴有发育迟缓，斜视和震颤

常染色体显性扭转性肌张力障碍1是一种外透性不全的疾病，通常是由TOR1A编码的内质网腔蛋白torsinA的框内GAG缺失（p.Glu303del）引起的。我们报告了一个纯合子显性疾病致TOR1A p.Glu303del突变，和一个新的纯合子错义变体（p.Gly318Ser）与严重的关节发育不良表型与发育迟缓，斜视和震颤在三个不相关的伊朗家庭的关联。担任TOR1A携带者的所有父母该变体没有显示出神经系统症状或体征的迹象，表明其外ance减少与常染色体显性遗传扭转性肌张力障碍1家族相似。细胞分析的结果表明，p.Gly318Ser取代引起了TorsinA从内质网到核膜的重新分布，类似于p.Glu303del突变的标志。我们的研究强调，严重关节置换患者应考虑TOR1A突变，并进一步扩大与TOR1A突变相关的表型谱。