Favorably skewed X-inactivation accounts for neurological sparing in female carriers of Menkes disease.
Classical Menkes disease is an X-linked recessive neurodegenerative disorder caused by mutations in ATP7A, which is located at Xq13.1-q21. ATP7A encodes a copper-transporting P-type ATPase and plays a critical role in development of the central nervous system. With rare exceptions involving sex chromosome aneuploidy or X-autosome translocations, female carriers of ATP7A mutations are asymptomatic except for subtle hair and skin abnormalities, although the mechanism for this neurological sparing has not been reported. We studied a three-generation family in which a severe ATP7A mutation, a 5.5-kb genomic deletion spanning exons 13 and 14, segregated. The deletion junction fragment was amplified from the proband by long-range polymerase chain reaction and sequenced to characterize the breakpoints. We screened at-risk females in the family for this junction fragment and analyzed their X-inactivation patterns using the human androgen-receptor (HUMARA) gene methylation assay. We detected the junction fragment in the proband, two obligate heterozygotes, and four of six at-risk females. Skewed inactivation of the X chromosome harboring the deletion was noted in all female carriers of the deletion (n = 6), whereas random X-inactivation was observed in all non-carriers (n = 2). Our results formally document one mechanism for neurological sparing in female carriers of ATP7A mutations. Based on review of X-inactivation patterns in female carriers of other X-linked recessive diseases, our findings imply that substantial expression of a mutant ATP7A at the expense of the normal allele could be associated with neurologic symptoms in female carriers of Menkes disease and its allelic variants, occipital horn syndrome, and ATP7A-related distal motor neuropathy.
Desai
V
V
Unit on Human Copper Metabolism, Molecular Medicine Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892-1832, USA.
Donsante
A
A
Swoboda
K J
KJ
Martensen
M
M
Thompson
J
J
Kaler
S G
SG
D000251:Adenosine Triphosphatases / Q000235:genetics; D000328:Adult; D027682:Cation Transport Proteins / Q000235:genetics; D041321:Chromosomes, Human, X / Q000235:genetics; D000073840:Copper-Transporting ATPases; D005260:Female; D017353:Gene Deletion; D005820:Genetic Testing; D006579:Heterozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D007706:Menkes Kinky Hair Syndrome / Q000235:genetics*; D010375:Pedigree; D049951:X Chromosome Inactivation / Q000235:genetics*; D055815:Young Adult
D027682:Cation Transport Proteins; D000251:Adenosine Triphosphatases; C081184:ATP7A protein, human; D000073840:Copper-Transporting ATPases