Strong P N, Brewster B S
Department of Paediatrics and Neonatal Medicine, Royal Postgraduate Medical School, Hammersmith Hospital, London, UK.
J Inherit Metab Dis. 1997 Jun;20(2):159-70. doi: 10.1023/a:1005396420442.
The mutation in the myotonic dystrophy (DM) gene is an expansion in a triplet (CTG) repeat in the 3' untranslated region of a novel gene that partially encodes a serine-threonine protein kinase (DMPK), with closest sequence homology to a small subgroup of protein kinases involved in the control of proliferation and cell shape. Expansion of the repeat correlates reasonably well with disease severity and offers a plausible molecular explanation for the previously contentious issue of anticipation. There is considerable heterogeneity in CTG expansion size in different tissues of affected individuals. The consensus of data from many laboratories indicates that DMPK mRNA is most probably downregulated as a consequence of the repeat expansion. Two polypeptides (68/78 kDa) have been shown to be absent in mouse knockout mutants and therefore can be considered as bona fide gene products. Previous data suggesting that 52-55 kDa polypeptides were likely candidates, have been firmly ruled out at the same time. Further results from studies of knockout and overexpressing transgenic mice indicate that neither simple loss nor gain of DMPK expression is sufficient to account for the DM clinical phenotype. One of the most pressing questions now being addressed is how expansion of the CTG repeat within the DMPK gene affects gene expression, not only of DMPK, but of all genes at the 19q13.3 locus: is DMPK actually responsible for the clinical phenotype seen in DM? The identification of both immediate upstream and downstream human genes (59 and DMRHP, respectively) has been an important first step to answering these questions. Only when these matters have been dealt with can one reasonably expect to start to delineate the different metabolic and signalling pathways responsible for the diverse phenotypes that make up the complex clinical picture of DM.
强直性肌营养不良（DM）基因的突变是一个新基因3'非翻译区中三联体（CTG）重复序列的扩增，该基因部分编码一种丝氨酸 - 苏氨酸蛋白激酶（DMPK），与参与增殖和细胞形态控制的一小类蛋白激酶具有最接近的序列同源性。重复序列的扩增与疾病严重程度有较好的相关性，并为之前有争议的遗传早现问题提供了一个合理的分子解释。在受影响个体的不同组织中，CTG扩增大小存在相当大的异质性。许多实验室的数据共识表明，重复序列扩增最有可能导致DMPK mRNA下调。已证明两种多肽（68/78 kDa）在小鼠基因敲除突变体中不存在，因此可被视为真正的基因产物。同时，之前认为52 - 55 kDa多肽可能是候选产物的数据已被明确排除。对基因敲除和过表达转基因小鼠的进一步研究结果表明，DMPK表达的简单缺失或增加都不足以解释DM的临床表型。目前正在解决的最紧迫问题之一是，DMPK基因内CTG重复序列的扩增如何影响基因表达，不仅是DMPK的表达，还有19q13.3位点所有基因的表达：DMPK是否真的是DM临床表型的原因？分别鉴定紧邻的上游和下游人类基因（分别为59和DMRHP）是回答这些问题的重要第一步。只有处理好这些问题，才有望合理地开始描绘导致构成DM复杂临床图景的各种表型的不同代谢和信号通路。
