Determining the role of skewed X-chromosome inactivation in developing muscle symptoms in carriers of Duchenne muscular dystrophy

Abstract

Duchenne and Becker dystrophinopathies (DMD and BMD) are X-linked recessive disorders caused by mutations in the dystrophin gene that lead to absent or reduced expression of dystrophin in both skeletal and heart muscles. DMD/BMD female carriers are usually asymptomatic, although about 8 % may exhibit muscle or cardiac symptoms. Several mechanisms leading to a reduced dystrophin have been hypothesized to explain the clinical manifestations and, in particular, the role of the skewed XCI is questioned. In this review, the mechanism of XCI and its involvement in the phenotype of BMD/DMD carriers with both a normal karyotype or with X;autosome translocations with breakpoints at Xp21 (locus of the DMD gene) will be analyzed. We have previously observed that DMD carriers with moderate/severe muscle involvement, exhibit a moderate or extremely skewed XCI, in particular if presenting with an early onset of symptoms, while DMD carriers with mild muscle involvement present a random XCI. Moreover, we found that among 87.1 % of the carriers with X;autosome translocations involving the locus Xp21 who developed signs and symptoms of dystrophinopathy such as proximal muscle weakness, difficulty to run, jump and climb stairs, 95.2 % had a skewed XCI pattern in lymphocytes. These data support the hypothesis that skewed XCI is involved in the onset of phenotype in DMD carriers, the X chromosome carrying the normal DMD gene being preferentially inactivated and leading to a moderate-severe muscle involvement.

Electrophysiological abnormalities in induced pluripotent stem cell‐derived cardiomyocytes generated from Duchenne muscular dystrophy patients

“…DMD female carriers are usually unaffected by dystrophin mutations because of skewed XCI preferably silencing the mutated allele . However, in this study we generated iPSC‐CMs from a heterozygous female manifesting carrier who presented severe adult onset DCM and myopathy.…”

“…DMD female carriers are usually unaffected by dystrophin mutations because of skewed XCI preferably silencing the mutated allele. 11 However, in this study we generated iPSC-CMs from a heterozygous female manifesting carrier who presented severe adult onset DCM and myopathy. Importantly, this woman carried a highly malignant out-of-frame deletion in the 5′ terminal of the DMD gene which caused a severe disease that resulted in teenage death of her son.…”

“…17,18 In this scenario, DMD female iPSC-CMs can be divided to two sub-populations: (1) cells expressing the WT allele, and (2) cells expressing the mutated allele. 11 Nonsense mediated decay of mRNA containing premature stop codon, reduces the amount of detectable mutated mRNA in the samples, thus hampering exact quantification of the ratio between these two sub-populations. 35 Nevertheless, our genetic analysis faithfully represents the two dystrophin alleles expression ratio in the iPSC-CM population used for the functional experiments.…”

“…iPSCs enable generation of human disease models to study underlying pathomechanisms in a cell type specific level. Previous studies investigating the effect of reprogramming on X chromosome status suggest three possible outcomes: (1) X chromosome inactivation (XCI) status is maintained throughout the reprogramming process; (2) inactivated X chromosome is reactivated; (3) inactivated X chromosome is eroded …”

Heart transplantation in patients with dystrophinopathic cardiomyopathy: Review of the literature and personal series

“…The onset of symptoms in DMD/BMD carriers may have several causes, the most frequent of them represented by a skewed X-chromosome inactivation (XCI) (26)(27)(28).…”