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Favorably skewed X-inactivation accounts for neurological sparing in female carriers of Menkes disease Desai V; Donsante A; Swoboda KJ; Martensen M; Thompson J; Kaler SGClin Genet 2011[Feb]; 79 (2): 176-82Classical 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.|Adenosine Triphosphatases/genetics[MESH]|Adult[MESH]|Cation Transport Proteins/genetics[MESH]|Chromosomes, Human, X/genetics[MESH]|Copper-Transporting ATPases[MESH]|Female[MESH]|Gene Deletion[MESH]|Genetic Testing[MESH]|Heterozygote[MESH]|Humans[MESH]|Infant[MESH]|Infant, Newborn[MESH]|Male[MESH]|Menkes Kinky Hair Syndrome/*genetics[MESH]|Pedigree[MESH]|X Chromosome Inactivation/*genetics[MESH]|Young Adult[MESH] |
