SHQ1 is essential for biogenesis of H/ACA ribonucleoproteins, a class of molecules important for processing ribosomal RNAs, modifying spliceosomal small nuclear RNAs, and stabilizing telomerase. Components of the H/ACA ribonucleoprotein complex have been linked to neurological developmental defects. Here we report two sibling pairs from unrelated families with compound heterozygous variants in SHQ1. Exome sequencing was used to detect disease causing variants which were submitted to ‘matching’ platforms linked to MatchMaker Exchange. Phenotype comparisons supported these matches. The affected individuals present with early-onset dystonia, with individuals from one family displaying additional neurological phenotypes, including neurodegeneration. As a result of CSF studies suggesting possible abnormal dopamine metabolism, a trial of levodopa replacement therapy was started but no clear response was noted. We show that fibroblasts from affected individuals have dramatic loss of SHQ1 protein. Variants from both families were expressed in S. cerevisiae, resulting in a strong reduction in H/ACA snoRNA production and remarkable defects in rRNA processing and ribosome formation. Our study identifies SHQ1 as associated with neurological disease, including early-onset dystonia, and begins to delineate the molecular etiology of this novel condition.

中文翻译：

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SHQ1 中的复合杂合变体与一系列神经学特征相关，包括早发性肌张力障碍

SHQ1 对 H/ACA 核糖核蛋白的生物发生至关重要，H/ACA 核糖核蛋白是一类对加工核糖体 RNA、修饰剪接体小核 RNA 和稳定端粒酶很重要的分子。H/ACA 核糖核蛋白复合物的成分与神经发育缺陷有关。在这里，我们报告了来自无关家庭的两对兄弟姐妹，在SHQ1中具有复合杂合变体. 外显子组测序用于检测提交给与 MatchMaker Exchange 链接的“匹配”平台的致病变异。表型比较支持这些匹配。受影响的个体患有早发性肌张力障碍，来自一个家庭的个体表现出额外的神经表型，包括神经变性。由于脑脊液研究表明多巴胺代谢可能异常，因此开始了左旋多巴替代疗法的试验，但没有发现明显的反应。我们显示来自受影响个体的成纤维细胞具有显着的 SHQ1 蛋白丢失。来自这两个家族的变体在酿酒酵母中表达，导致 H/ACA snoRNA 产生的强烈减少以及 rRNA 加工和核糖体形成的显着缺陷。我们的研究确定SHQ1与神经系统疾病相关，包括早发性肌张力障碍，并开始描述这种新疾病的分子病因。