MAPPING OF THE MENKES LOCUS TO XQ13.3 DISTAL TO THE X-INACTIVATION CENTER BY AN INTRACHROMOSOMAL INSERTION OF THE SEGMENT XQ13.3-Q21.2

During a systematic chromosomal survey of 167 unrelated boys with the X-linked recessive Menkes disease (MIM 309400), a unique rearrangement of the X chromosome was detected, involving an insertion of the long arm segment Xq13.3-q21.2 into the short arm at band Xp11.4, giving the karyotype 46,XY,ins(X) (p11.4q13.3q21.2). The same rearranged X chrom osome was present de novo in the subject's phenotypically normal mothe r, where it was preferentially inactivated. The restriction fragment l ength polymorphism and methylation patterns at DXS255 indicated that t he rearrangement originated from the maternal grandfather. Together wi th a previously described X; autosomal translocation in a female Menke s patient, the present finding supports the localization of the Menkes locus (MNK) to Xq13, with a suggested fine mapping to sub-band Xq13.3 . This localization is compatible with linkage data in both man and mo use. The chromosomal bend associated with the X-inactivation center (X IC) was present on the proximal long arm of the rearranged X chromosom e, in line with a location of XIC proximal to MNK. Combined data sugge st the following order: Xcen-XIST(XIC), DXS128-DXS171, DXS56-MNK-PGK1- Xqter.