MacLean H E, Warne G L, Zajac J D
Centre for Hormone Research, Royal Children's Hospital, Parkville, Victoria, Australia.
J Neurol Sci. 1996 Feb;135(2):149-57. doi: 10.1016/0022-510x(95)00284-9.
Kennedy's disease (spinal and bulbar muscular atrophy) is an X-linked form of motor neuron disease that affects adult men. The syndrome is characterized by progressive atrophy of the limb muscles, pelvic and shoulder girdles and dysphagia and dysarthria, and is caused by the degeneration of spinal and bulbar motor neurons. Kennedy's disease is caused by a trinucleotide repeat expansion of a CAG repeat in exon A of the androgen receptor gene, and is one of a group of neurological diseases caused by trinucleotide repeat expansions in different genes. The mutation in Kennedy's disease involves an increased number of glutamine residues in the amino-terminal domain of the receptor. Point mutations and deletions in the androgen receptor gene cause androgen insensitivity syndrome, however subjects with Kennedy's disease have normal virilization, although progressive gynaecomastia, testicular atrophy and infertility may occur. Androgen receptors are expressed widely in the normal brain, and in the anterior horn cells of the spinal cord; however, their role in neuronal tissue is not known, nor is it known how the androgen receptor gene mutation causes neuronal degeneration. Kennedy's disease is likely to be a 'gain of function' abnormality, so that the presence of the receptor with an increased number of glutamines is toxic to motor neurons. It is possible that the mutation alters interaction of the receptor with other neuronal transcription factors, or neuronotoxicity may occur because of a non-specific effect caused by the presence of a protein with a large homoglutamine domain. Studies of patients with Kennedy's disease have shown that expression of androgen receptor mRNA and protein in spinal cord may be decreased, as can be the affinity of the mutant receptor for androgen. In vitro studies have shown impaired transcription activation ability of the mutant androgen receptor. The age at onset of Kennedy's disease may correlate with the size of the CAG repeat, however there is a large degree of variability of age at onset between subjects with the same number of repeats. Further study of the effect of the Kennedy's disease mutation on androgen receptor function in motor neurons will allow us to increase our understanding of the pathogenesis of this disease.
肯尼迪病（脊髓延髓肌萎缩症）是一种影响成年男性的X连锁型运动神经元病。该综合征的特征为肢体肌肉、骨盆带和肩胛带进行性萎缩，以及吞咽困难和构音障碍，由脊髓和延髓运动神经元变性所致。肯尼迪病由雄激素受体基因外显子A中CAG重复序列的三核苷酸重复扩增引起，是由不同基因中的三核苷酸重复扩增导致的一组神经疾病之一。肯尼迪病中的突变涉及受体氨基末端结构域中谷氨酰胺残基数量增加。雄激素受体基因中的点突变和缺失会导致雄激素不敏感综合征，然而肯尼迪病患者具有正常的男性化特征，尽管可能会出现进行性男性乳房发育、睾丸萎缩和不育。雄激素受体在正常大脑和脊髓前角细胞中广泛表达；然而，它们在神经元组织中的作用尚不清楚，雄激素受体基因突变如何导致神经元变性也不清楚。肯尼迪病可能是一种“功能获得性”异常，因此含有增加数量谷氨酰胺的受体对运动神经元有毒性。有可能该突变改变了受体与其他神经元转录因子的相互作用，或者由于含有大的同聚谷氨酰胺结构域的蛋白质的存在引起的非特异性效应而可能发生神经元毒性。对肯尼迪病患者的研究表明，脊髓中雄激素受体mRNA和蛋白的表达可能会降低，突变受体对雄激素的亲和力也可能降低。体外研究表明突变型雄激素受体的转录激活能力受损。肯尼迪病的发病年龄可能与CAG重复序列的大小相关，然而，具有相同重复次数的个体之间发病年龄存在很大差异。进一步研究肯尼迪病突变对运动神经元中雄激素受体功能的影响将使我们能够增进对该疾病发病机制的理解。
