A female carrier of a novel DMD mutation with slightly skewed X-chromosome inactivation shows a suspected case of Becker muscular dystrophy in a Chinese family

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.