title: X-linked Menkes disease: first documented report of germ-line mosaicism.
abstract: This work investigated a three-generation Menkes disease family, where germ-line mosaicism was suspected in the maternal grandmother of the index patient. She had given birth to 2 boys who died of suspected Menkes disease on the basis of clinical and photographic evidence. Biochemical analysis of the index patient confirmed the diagnosis of Menkes disease, and DNA analysis established a partial gene deletion (EX11_EX23del), involving exons 11-23 and the 3'-untranslated region (UTR) of ATP7A. A junction fragment was detectable by Southern blot analysis, which enabled carrier analysis. The mother was demonstrated to be a carrier, whereas analysis of lymphoblasts and skin fibroblasts from the maternal grandmother gave no indication of a partial gene deletion. No materials were available from the possibly affected maternal uncles. Further genetic analyses, including biochemical testing of the grandmother and haplotype analysis using four intragenic markers on DNA from selected members of the family, corroborated this finding. The combined results from DNA analyses showed that the grandmother had transmitted three different ATP7A haplotypes to her offspring: (1) the at-risk allele (CA(B))-1 and the deletion; (2) the at-risk allele (CA(B))-1 without deletion; and (3) the second allele (CAB)-2 without deletion. In conclusion, our study demonstrated segregation of Menkes disease within the family investigated that can best be explained by extensive germ-line mosaicism in the maternal grandmother. The finding of germ-line mosaicism has obvious implications for genetic counseling of Menkes disease families.
authors.affiliation: Medical Genetics Laboratory Center, The John F. Kennedy Institute, Glostrup, Denmark.
authors.forename: Lena
authors.initials: L
authors.lastname: Poulsen
authors.forename: Lisbeth Birk
authors.initials: LB
authors.lastname: Møller
authors.forename: Katie
authors.initials: K
authors.lastname: Plunkett
authors.forename: John
authors.initials: J
authors.lastname: Belmont
authors.forename: Zeynep
authors.initials: Z
authors.lastname: Tümer
authors.forename: Nina
authors.initials: N
authors.lastname: Horn
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics*; D001692:Biological Transport / Q000235:genetics; D027682:Cation Transport Proteins / Q000235:genetics*; D002478:Cells, Cultured; D003300:Copper / Q000378:metabolism; D000073840:Copper-Transporting ATPases; D005260:Female; D005347:Fibroblasts / Q000502:physiology; D017353:Gene Deletion; D018095:Germ-Line Mutation; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008297:Male; D007706:Menkes Kinky Hair Syndrome / Q000235:genetics*; D009030:Mosaicism; D010375:Pedigree; D011993:Recombinant Fusion Proteins / Q000235:genetics*
chemical_list: D027682:Cation Transport Proteins; D011993:Recombinant Fusion Proteins; D003300:Copper; D000251:Adenosine Triphosphatases; C081184:ATP7A protein, human; D000073840:Copper-Transporting ATPases