Autosomal-Dominant Striatal Degeneration Is Caused by a Mutation in the Phosphodiesterase 8B Gene
Autosomal-Dominant Striatal Degeneration Is Caused by a Mutation in the Phosphodiesterase 8B Gene
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DOI：
10.1016/j.ajhg.2009.12.003
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发表时间：
2010-01-08
影响因子：
9.8
通讯作者：
Kuhlenbaeumer, Gregor
中科院分区：
文献类型：
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作者：
Appenzeller, Silke;Schirmacher, Anja;Kuhlenbaeumer, Gregor
常染色体显性纹状体变性（ADSD）是一种影响基底神经节纹状体部分的常染色体显性运动障碍。ADSD的特征是运动迟缓、构音障碍和肌肉僵硬。这些症状类似于特发性帕金森病，但不存在震颤。利用遗传连锁分析，我们已经将致病性遗传缺陷定位到染色体5q13.3-q14.1上的3.25兆碱基的候选区域。在标记DSS 1962处获得的最大LOD评分为4.1（θ = 0）。在这里，我们表明，ADSD是由磷酸二酯酶8B（PDE 8B）基因中的复杂移码突变（c.94G>C+c.95delT）引起的，这导致磷酸二酯酶酶活性的丧失。我们发现PDF 8B在大脑中高度表达，特别是在受ADSD影响的壳核中。PDE 8B降解环AMP，这是多巴胺信号传导中的第二信使。多巴胺是参与运动控制的主要神经递质之一，在帕金森病中缺乏。我们相信，对PDE 8B的功能分析将有助于进一步阐明ADSD的病理机制，并有助于更好地理解运动障碍。
Autosomal-dominant striatal degeneration (ADSD) is an autosomal-dominant movement disorder affecting the striatal part of the basal ganglia. ADSD is characterized by bradykinesia, dysarthria, and Muscle rigidity. These symptoms resemble idiopathic Parkinson disease, but tremor is not present. Using genetic linkage analysis, we have mapped the causative genetic defect to a 3.25 megabase candidate region on chromosome 5q13.3-q14.1. A maximum LOD score of 4.1 (Theta = 0) was obtained at marker DSS1962. Here we show that ADSD is caused by a complex frameshift mutation (c.94G>C+c.95delT) in the phosphodiesterase 8B (PDE8B) gene, which results in a loss of enzymatic phosphodiesterase activity. We found that PDF8B is highly expressed in the brain, especially in the putamen, which is affected by ADSD. PDE8B degrades cyclic AMP, a second messenger implied in dopamine signaling. Dopamine is one of the main neurotransmitters involved in movement control and is deficient in Parkinson disease. We believe that the functional analysis of PDE8B will help to further elucidate the pathomechanism of ADSD as well as contribute to a better understanding of movement disorders.