The aetiology of dystonia disorders is complex, and next-generation sequencing has become a useful tool in elucidating the variable genetic background of these diseases. Here we report a deleterious heterozygous truncating variant in the inosine monophosphate dehydrogenase gene (IMPDH2) by whole-exome sequencing, co-segregating with a dominantly inherited dystonia-tremor disease in a large Finnish family. We show that the defect results in degradation of the gene product, causing IMPDH2 deficiency in patient cells. IMPDH2 is the first and rate-limiting enzyme in the de novo biosynthesis of guanine nucleotides, a dopamine synthetic pathway previously linked to childhood or adolescence-onset dystonia disorders. We report IMPDH2 as a new gene to the dystonia disease entity. The evidence underlines the important link between guanine metabolism, dopamine biosynthesis and dystonia.

肌张力障碍的病因很复杂，二代测序已成为阐明这些疾病可变遗传背景的有用工具。在这里，我们通过全外显子组测序报告了肌苷一磷酸脱氢酶基因 ( IMPDH2 ) 中的有害杂合截断变体，它与芬兰一个大家族中的显性遗传性肌张力障碍-震颤疾病共同分离。我们表明该缺陷会导致基因产物降解，从而导致患者细胞中的 IMPDH2 缺乏。IMPDH2 是鸟嘌呤核苷酸从头生物合成中的第一个和限速酶，鸟嘌呤核苷酸是一种多巴胺合成途径，以前与儿童或青春期发病的肌张力障碍有关。我们报告IMPDH2作为肌张力障碍疾病实体的新基因。证据强调了鸟嘌呤代谢、多巴胺生物合成和肌张力障碍之间的重要联系。