A catechol-O-methyltransferase that is essential for auditory function in mice and humans
A catechol-O-methyltransferase that is essential for auditory function in mice and humans
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DOI：
10.1073/pnas.0807219105
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发表时间：
2008-09-23
影响因子：
11.1
通讯作者：
Beutler, Bruce
中科院分区：
文献类型：
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作者：
Du, Xin;Schwander, Martin;Beutler, Bruce
我们已经确定了一个以前未注释的儿茶酚-O-甲基转移酶（COMT），在这里指定COMT 2，通过定位克隆的化学诱导突变负责的神经行为表型。Comt 2错义突变纯合子小鼠表现出前庭功能障碍、深度感觉神经性耳聋和Corti器官进行性变性。与这种表型一致，COMT 2在内耳的感觉毛细胞中高度表达。COMT 2酶活性显着降低的错义突变，这表明，在儿茶酚胺catalysts缺陷的基础上的听觉和前庭表型。基于对小鼠的研究，我们筛选了来自人类家族的DNA，并确定了导致非综合征性耳聋的小鼠Comt 2基因的人类直系同源物中的无义突变。COMT对儿茶酚胺修饰的缺陷以前曾与精神分裂症的发展有关。我们的研究确定了一个以前未描述的COMT基因，并指出了一个意想不到的作用，儿茶酚胺在听觉和前庭感觉器官的功能。
We have identified a previously unannotated catechol-O-methyltranferase (COMT), here designated COMT2, through positional cloning of a chemically induced mutation responsible for a neurobehavioral phenotype. Mice homozygous for a missense mutation in Comt2 show vestibular impairment, profound sensorineuronal deafness, and progressive degeneration of the organ of Corti. Consistent with this phenotype, COMT2 is highly expressed in sensory hair cells of the inner ear. COMT2 enzymatic activity is significantly reduced by the missense mutation, suggesting that a defect in catecholamine catabolism underlies the auditory and vestibular phenotypes. Based on the studies in mice, we have screened DNA from human families and identified a nonsense mutation in the human ortholog of the murine Comt2 gene that causes nonsyndromic deafness. Defects in catecholamine modification by COMT have been previously implicated in the development of schizophrenia. Our studies identify a previously undescribed COMT gene and indicate an unexpected role for catecholamines in the function of auditory and vestibular sense organs.