Myotonic dystrophy: molecular windows on a complex etiology.
Myotonic dystrophy: molecular windows on a complex etiology.
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DOI：
10.1093/nar/26.6.1363
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发表时间：
1998-03
影响因子：
14.9
通讯作者：
Zeljka Korade-Mirnics;E. Hoffman;P. Babitzke
中科院分区：
文献类型：
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作者：
Zeljka Korade-Mirnics;E. Hoffman;P. Babitzke
强直性肌营养不良症(DM)是最常见的成人型肌营养不良症，发病率约为1/8500。糖尿病是由cAMP依赖的蛋白激酶(DM Protein Kinase，DMPK)的3‘-非翻译区(UTR)中三核苷酸重复数增加引起的。虽然已经产生了大量具有不同基因结构和敲除的转基因动物，但没有一种能忠实地概括人类患者中看到的多系统且通常是严重的表型。转基因数据表明，强直性肌营养不良并不是简单地由DM激酶基因产物的生化缺陷或异常引起的。新出现的研究表明，两种新的致病机制可能在该病中发挥作用：扩大的重复似乎导致邻近的同源盒基因单倍性不足，以及异常的DMPK RNA似乎对RNA动态平衡产生不利影响。这种复杂的、多系统的表型可能反映了一种潜在的多方面的分子病理生理学：面部畸形可能是由于同源盒基因单倍体不足引起的模式缺陷，而肌肉疾病和内分泌异常可能是由于RNA代谢改变和cAMP DMPK蛋白缺乏引起的。
Myotonic dystrophy (DM) is the most common form of adult onset muscular dystrophy, with an incidence of approximately 1 in 8500 adults. DM is caused by an expanded number of trinucleotide repeats in the 3'-untranslated region (UTR) of a cAMP-dependent protein kinase (DM protein kinase, DMPK). Although a large number of transgenic animals have been generated with different gene constructions and knock-outs, none of them faithfully recapitulates the multisystemic and often severe phenotype seen in human patients. The transgenic data suggest that myotonic dystrophy is not caused simply by a biochemical deficiency or abnormality in the DM kinase gene product. Emerging studies suggest that two novel pathogenetic mechanisms may play a role in the disease: the expanded repeats appear to cause haploinsufficiency of a neighboring homeobox gene and also abnormal DMPK RNA appears to have a detrimental effect on RNA homeostasis. The complex, multisystemic phenotype may reflect an underlying multifaceted molecular pathophysiology: the facial dysmorphology may be due to pattern defects caused by haploinsufficiency of the homeobox gene, while the muscle disease and endocrine abnormalities may be due to both altered RNA metabolism and deficiency of the cAMP DMPK protein.