Proteolipoprotein gene analysis in 82 patients with sporadic Pelizaeus-Merzbacher disease: Duplications, the major cause of the disease, originate more frequently in male germ cells, but point mutations do not

Pelizaeus-Merzbacher Disease (PMD) is an X-linked developmental defect of m yelination affecting the central nervous system and segregating with the pr oteolipoprotein (PLP) locus. Investigating 82 strictly selected sporadic ca ses of PMD, we found PLP mutations in 77%; complete PLP-gene duplications w ere the most frequent abnormality (62%), whereas point mutations in coding or splice-site regions of the gene were involved less frequently (38%). We analyzed the maternal both types of status of 56 cases to determine the ori gin ofPLP mutation, since this is relevant to genetic counseling. In the 22 point mutations, 68% of mothers were heterozygous for the mutation, a valu e identical to the two-thirds of carrier mothers that would be expected if there were an equal mutation rate in male and female germ cells. In sharp c ontrast, among the 34 duplicated cases, 91% of mothers were carriers, a val ue significantly (chi(2) = 9.20, P < .01) in favor of a male bias, with an estimation of the male/female mutation frequency (k) of 3.3. Moreover, we o bserved the occurrence of de novo mutations between parental and grandparen tal generations in 17 three-generation families, which allowed a direct est imation of the k value (k = 11). Again, a significant male mutation imbalan ce was observed only for the duplications. The mechanism responsible for th is strong male bias in the duplications may involve an unequal sister chrom atid exchange, since two deletion events, responsible for mild clinical man ifestations, have been reported in PLP-related diseases.