De Novo Mutations in PDE1 0A Cause Childhood-Onset Chorea with Bilateral Striatal Lesions
De Novo Mutations in PDE1 0A Cause Childhood-Onset Chorea with Bilateral Striatal Lesions
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DOI：
10.1016/j.ajhg.2016.02.015
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发表时间：
2016-04-07
影响因子：
9.8
通讯作者：
Bhatia, Kailash P.
中科院分区：
文献类型：
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作者：
Mencacci, Niccolo E.;Kamsteeg, Erik-Jan;Bhatia, Kailash P.
舞蹈病是一种多动性运动障碍，由纹状体中型多棘神经元 (MSN) 功能障碍引起，纹状体中型棘神经元构成基底神经节的主要输出投射。在这里，我们使用全外显子组测序来揭示三个不相关个体的潜在遗传原因，这些个体具有非常相似且独特的儿童期舞蹈病临床表现，特征性脑 MRI 显示对称双侧纹状体病变。所有个体均被鉴定为 PDE10A 携带从头杂合突变（两个个体中为 c.898T>C [p.Phe300Leu]，一个个体中为 c.1000T>C [p.Phe334Leu]），编码一种高度选择性地存在于 MSN 中的磷酸二酯酶。 PDE10A 有助于调节环磷酸腺苷 (cAMP) 和环磷酸鸟苷 (cGMP) 的细胞内水平。两种取代都会影响位于调节性 GAF-B 结构域中的高度保守的氨基酸，该氨基酸通过与 cAMP 结合，刺激 PDE10A 催化结构域的活性。计算机模型显示，改变的残基位于结合袋深处，它们可能会改变 cAMP 结合特性。体外功能研究表明，两种取代均不会影响 PDE10A 的基础活性，但会严重破坏 cAMP 与 GAF-B 结构域结合介导的刺激作用。 PDE10A 突变作为舞蹈病病因的鉴定进一步推动了 MSN 中 cAMP 信号传导的研究，并强调了纹状体 cAMP 信号传导在基底神经节回路调节中的关键作用。该途径的药理学调节可以为舞蹈症和其他多动性运动障碍提供有希望的病因学靶向治疗。
Chorea is a hyperkinetic movement disorder resulting from dysfunction of striatal medium spiny neurons (MSNs), which form the main output projections from the basal ganglia Here, we used whole-exome sequencing to unravel the underlying genetic cause in three unrelated individuals with a very similar and unique clinical presentation of childhood-onset chorea and characteristic brain MRI showing symmetrical bilateral striatal lesions. All individuals were identified to carry a de novo heterozygous mutation in PDE10A (c.898T>C [p.Phe300Leu] in two individuals and c.1000T>C [p.Phe334Leu] in one individual), encoding a phosphodiesterase highly and selectively present in MSNs. PDE10A contributes to the regulation of the intracellular levels of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Both substitutions affect highly conserved amino acids located in the regulatory GAF-B domain, which, by binding to cAMP, stimulates the activity of the PDE10A catalytic domain. In silico modeling showed that the altered residues are located deep in the binding pocket, where they are likely to alter cAMP binding properties. In vitro functional studies showed that neither substitution affects the basal PDE10A activity, but they severely disrupt the stimulatory effect mediated by cAMP binding to the GAF-B domain. The identification of PDE10A mutations as a cause of chorea further motivates the study of cAMP signaling in MSNs and highlights the crucial role of striatal cAMP signaling in the regulation of basal ganglia circuitry. Pharmacological modulation of this pathway could offer promising etiologically targeted treatments for chorea and other hyperkinetic movement disorders.