X inactivation phenotype in carriers of Pelizaeus-Merzbacher disease: skewed in carriers of a duplication and random in carriers of point mutations

Pelizaeus-Merzbacher disease (PMD) is an X-linked recessive disease caused by coding sequence mutations in the PLP gene, sub-microscopic duplications of variable sizes including the PLP gene or very rarely deletions of the PL P gene. We analysed the X inactivation pattern in blood of PMD female carri ers with duplications and with point mutations. In the majority of duplicat ion carriers (7/11), the X chromosome bearing the duplication was preferent ially inactivated, whereas a random pattern of X inactivation was detected in point mutation carriers (3/3), a deletion carrier (1/1), affected female s (4/4) who did not have a recognised mutation and normal control females. However 2/5 non-carrier female relatives of patients with a duplication, ha d skewed X inactivation. The skewed pattern of inactivation observed in mos t duplication carriers and not in mutation carriers suggests a) that there is selection against those cells in which the duplicated X chromosome is ac tive and b) other expressed sequences within the duplicated region rather t han mutant PLP may be responsible. Since the skewed X inactivation did not segregate with the disease in two families and the pattern of X inactivatio n was variable among the duplication carriers, the pattern X inactivation i s an unsuitable diagnostic tool for female carriers of PMD.