Prior T W, Bartolo C, Pearl D K, Papp A C, Snyder P J, Sedra M S, Burghes A H, Mendell J R
Department of Pathology, Ohio State University, Columbus 43210, USA.
Am J Hum Genet. 1995 Jul;57(1):22-33.
Duchenne and Becker muscular dystrophies (DMD and BMD) are caused by defects in the dystrophin gene. About two-thirds of the affected patients have large deletions or duplications, which occur in the 5' and central portion of the gene. The nondeletion/duplication cases are most likely the result of smaller mutations that cannot be identified by current diagnostic screening strategies. We screened approximately 80% of the dystrophin coding sequence for small mutations in 158 patients without deletions or duplications and identified 29 mutations. The study indicates that many of the DMD and the majority of the BMD small mutations lie in noncoding regions of the gene. All of the mutations identified were unique to single patients, and most of the mutations resulted in protein truncation. We did not find a clustering of small mutations similar to the deletion distribution but found > 40% of the small mutations 3' of exon 55. The extent of protein truncation caused by the 3' mutations did not determine the phenotype, since even the exon 76 nonsense mutation resulted in the severe DMD phenotype. Our study confirms that the dystrophin gene is subject to a high rate of mutation in CpG sequences. As a consequence of not finding any hotspots or prevalent small mutations, we conclude that it is presently not possible to perform direct carrier and prenatal diagnostics for many families without deletions or duplications.
杜兴氏和贝克氏肌营养不良症（DMD和BMD）由肌营养不良蛋白基因缺陷引起。约三分之二的患病患者存在大片段缺失或重复，这些发生在基因的5'端和中部。非缺失/重复病例很可能是目前诊断筛查策略无法识别的较小突变导致的。我们在158例无缺失或重复的患者中筛查了约80%的肌营养不良蛋白编码序列以寻找小突变，并鉴定出29个突变。该研究表明，许多DMD和大多数BMD小突变位于基因的非编码区。所有鉴定出的突变都是单个患者所特有的，并且大多数突变导致蛋白质截短。我们没有发现类似于缺失分布的小突变聚集现象，但发现超过40%的小突变位于外显子55的3'端。3'端突变导致的蛋白质截短程度并不能决定表型，因为即使是外显子76无义突变也导致严重的DMD表型。我们的研究证实，肌营养不良蛋白基因在CpG序列中突变率很高。由于未发现任何热点或普遍存在的小突变，我们得出结论，目前对于许多无缺失或重复的家庭来说，无法进行直接的携带者和产前诊断。
