Figure 3
From: Unfavorable switching of skewed X chromosome inactivation leads to Menkes disease in a female infant
Unfavorable switching of skewed XCI in the proband. (A) XCI analysis by methylation-sensitive PCR targeting the HUMARA locus. Genomic DNA from peripheral blood of the proband had 278-bp and 281-bp fragments, the former from her father, and the latter from her mother and her grandmother. The inheritance pattern of the 281-bp allele is consistent with the deletion status of the ATP7A gene, suggesting that the 281-bp allele represents the deleted ATP7A gene allele. While the grandmother and the mother show moderate (81:19) and extreme (95:5), respectively, skewing of XCI toward the 281-bp allele with the ATP7A deletion, the proband has extremely skewed XCI (99.3:0.7) toward the normal 278-bp allele. (B) XCI analysis of the hair (two samples) and the right (Rt.) and left (Lt.) buccal mucosa of the proband (upper) and the mother (lower), showing a consistent trend of skewed XCI in each individual. (C) RNA sequencing of peripheral blood cells of the proband, the father, the mother, and the grandmother (GraMo). The upper grey tracks show coverage depth, and the lower dark red tracks show junctions of RNA sequencing. The proband exclusively expressed the pathogenic ATP7A mRNA transcripts lacking exons 16 and 17. Two asterisks indicate no coverage of exons 16 and 17 in the proband.
