Interdisciplinary Program in Biomedical Sciences and Department of Neurology, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
Hum Mol Genet. 2012 Sep 15;21(18):3984-92. doi: 10.1093/hmg/dds221. Epub 2012 Jun 7.
Restless legs syndrome (RLS), also known as Willis-Ekbom disease, is a sensory-motor neurological disorder with a circadian component. RLS is characterized by uncomfortable sensations in the extremities, generally at night or during sleep, which often leads to an uncontrollable urge to move them for relief. Recently, genomic studies identified single-nucleotide polymorphisms in BTBD9, along with three other genes, as being associated with a higher risk of RLS. Little is known about the function of BTBD9 or its potential role in the pathophysiology of RLS. We therefore examined a line of Btbd9 mutant mice we recently generated for phenotypes similar to symptoms found in RLS patients. We observed that the Btbd9 mutant mice had motor restlessness, sensory alterations likely limited to the rest phase, and decreased sleep and increased wake times during the rest phase. Additionally, the Btbd9 mutant mice had altered serum iron levels and monoamine neurotransmitter systems. Furthermore, the sensory alterations in the Btbd9 mutant mice were relieved using ropinirole, a dopaminergic agonist widely used for RLS treatment. These results, taken together, suggest that the Btbd9 mutant mice model several characteristics similar to RLS and would therefore be the first genotypic mouse model of RLS. Furthermore, our data provide further evidence that BTBD9 is involved in RLS, and future studies of the Btbd9 mutant mice will help shine light on its role in the pathophysiology of RLS. Finally, our data argue for the utility of Btbd9 mutant mice to discover and screen novel therapeutics for RLS.
不宁腿综合征（RLS），又称 Willis-Ekbom 病，是一种具有昼夜节律成分的感觉运动性神经系统疾病。RLS 的特征是肢体出现不适感，通常在夜间或睡眠时出现，这常常导致不可控制的移动肢体以缓解不适。最近，基因组研究确定了 BTBD9 中的单核苷酸多态性，以及另外三个基因，与 RLS 的更高风险相关。BTBD9 的功能或其在 RLS 病理生理学中的潜在作用知之甚少。因此，我们检查了最近生成的一系列 Btbd9 突变小鼠，以观察其是否具有类似于 RLS 患者症状的表型。我们观察到 Btbd9 突变小鼠出现运动不安、感觉改变（可能仅限于休息期）、睡眠减少和休息期觉醒时间增加。此外，Btbd9 突变小鼠的血清铁水平和单胺能神经递质系统发生改变。此外，使用罗匹尼罗（一种广泛用于 RLS 治疗的多巴胺激动剂）可缓解 Btbd9 突变小鼠的感觉改变。这些结果表明，Btbd9 突变小鼠模型具有类似于 RLS 的多种特征，因此将成为首个 RLS 的基因型小鼠模型。此外，我们的数据进一步证明 BTBD9 参与 RLS，对 Btbd9 突变小鼠的未来研究将有助于阐明其在 RLS 病理生理学中的作用。最后，我们的数据表明 Btbd9 突变小鼠可用于发现和筛选 RLS 的新型治疗方法。
