Abstract：
Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are both caused by mutations in DMD gene effecting the expression of dystrophin. Generally female carriers are asymptomatic; however, it has been suggested that carriers may exhibit symptoms. We investigated a 6-year-old Chinese girl exhibiting a suspected BMD phenotype, including persistently elevated creatine kinase and creatine kinase isoenzyme levels. The proband harbored a novel heterozygous mutation, c.3458_3459insAA, within exon 26 of the DMD gene inherited from her mother who had a completely normal phenotype and presented with mosaicism in her lymphocytes with 45, X [17%]/46, XX [83%]. In addition, X-chromosome inactivation (XCI) patterns in the peripheral blood of the child were slightly skewed: proband with 62% (mutant allele)/38% (normal allele) when compared with her mother with 32/68%. Amplification of regions of the cDNA revealed different ratios for the expression of these alleles: proband with 50/50% and her mother with 20/80%. Real-time PCR showed that mRNA expression was significantly decreased in both. We proposed that a frameshift or nonsense mutation may contribute to the development of symptoms in carriers. These phenotypes correlate with nonrandom XCI patterns and are compounded by the locus of the mutation. For incompletely skewed XCI patterns, although the mutant allele could suppress the expression of a normal allele, carriers would remain asymptomatic as long as there was adequate compensation from the normal allele. We also proposed a mechanism where mRNA from the mutant allele may be unstable and easily degraded, allowing for phenotypic compensation by the wildtype allele.
摘要：
Duchenne型肌营养不良(DMD)和Becker型肌营养不良(BMD)都是由DMD基因突变影响肌营养不良蛋白表达引起的。一般来说，女性携带者是无症状的；然而，有人建议携带者可能会出现症状。我们调查了一名6岁的中国女孩，她表现出可疑的BMD表型，包括持续升高的肌酸激酶和肌酸激酶同工酶水平。先证者有一个新的杂合突变，c.3458_3459insAA,在DMD基因的第26外显子内遗传自母亲，她的母亲具有完全正常的表型，并在她的淋巴细胞中以45,X[17％]/46,XX[83％]呈现镶嵌性。此外,儿童外周血中的X染色体失活（XCI）模式略有偏斜：与母亲的32/68％相比，先证者为62％（突变等位基因）/38％（正常等位基因）。cDNA区域的扩增显示这些等位基因的表达比例不同：先证者为50/50％，母亲为20/80％。实时荧光定量PCR显示两者的mRNA表达均显著降低。我们提出移码或无义突变可能有助于携带者症状的发展。这些表型与非随机XCI模式相关，并因突变的基因座而复杂化。对于不完全偏斜的XCI模式，尽管突变等位基因可以抑制正常等位基因的表达，只要正常等位基因有足够的补偿，携带者将保持无症状。我们还提出了一种机制，其中来自突变等位基因的mRNA可能不稳定且容易降解，允许通过野生型等位基因进行表型补偿。
