Roberts R G, Gardner R J, Bobrow M
Paediatric Research Unit, Guy's Hospital, London, England.
Hum Mutat. 1994;4(1):1-11. doi: 10.1002/humu.1380040102.
The past few years have seen a rapid increase in our knowledge of naturally occurring mutations in the dystrophin gene. Although earlier studies were limited to gross rearrangement mutations, we are now in a position to draw lessons on the molecular etiology of the remaining one-third of cases of Duchenne and Becker muscular dystrophy (DMD, BMD) which are associated with small mutations. This paper reviews 70 published and unpublished small mutations in the dystrophin gene and asks what we can learn about their nature, their distribution, and approaches to their characterisation. Strikingly for such a well-conserved gene, missense mutations are extremely rare, and the vast majority of DMD point mutations, like the gross rearrangements, result in premature translational termination. It seems increasingly likely that almost all cases of DMD arise solely as a result of a reduction in the level of dystrophin transcripts, and we argue that > 95% of DMD mutations contribute nothing to the functional dissection of the dystrophin protein. Most of the few BMD point mutations presented here are missense mutations in the N-terminal or C-terminal domains or are splice-site mutations that probably act, like BMD deletions, via the production of in-frame, interstitially deleted transcripts.
在过去几年中，我们对肌营养不良蛋白基因中自然发生的突变的了解迅速增加。尽管早期研究仅限于大规模重排突变，但现在我们能够从与小突变相关的杜兴氏和贝克氏肌营养不良症（DMD、BMD）其余三分之一病例的分子病因中吸取教训。本文回顾了肌营养不良蛋白基因中70个已发表和未发表的小突变，并探讨了我们能从它们的性质、分布以及表征方法中学到什么。对于这样一个高度保守的基因而言，错义突变极为罕见，并且绝大多数DMD点突变，如同大规模重排一样，会导致翻译提前终止。几乎所有DMD病例似乎越来越有可能仅仅是由于肌营养不良蛋白转录本水平降低所致，并且我们认为超过95%的DMD突变对肌营养不良蛋白的功能剖析没有贡献。这里呈现的少数BMD点突变大多是N端或C端结构域中的错义突变，或者是剪接位点突变，它们可能像BMD缺失一样，通过产生框内、间隙缺失的转录本来发挥作用。
