Favorably skewed X-inactivation accounts for neurological sparing in female carriers of Menkes disease

• Published in: Clinical genetics Vol. 79; no. 2; pp. 176 - 182
• Main Authors: Desai, V, Donsante, A, Swoboda, KJ, Martensen, M, Thompson, J, Kaler, SG
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-02-2011; Wiley-Blackwell
• Subjects: Adenosine Triphosphatases - genetics; Adult; ATP7A; Biological and medical sciences; Cation Transport Proteins - genetics; Chromosomes, Human, X - genetics; Copper-transporting ATPases; Disease; Female; Females; Fundamental and applied biological sciences. Psychology; Gene Deletion; General aspects. Genetic counseling; Genetic disorders; Genetic Testing; Genetics of eukaryotes. Biological and molecular evolution; Heterozygote; Humans; Indexing in process; Infant; Infant, Newborn; junction fragment; Male; Medical genetics; Medical sciences; Menkes disease; Menkes Kinky Hair Syndrome - genetics; Metabolic diseases; Metals (hemochromatosis...); Molecular and cellular biology; Neurological disorders; Other metabolic disorders; Pedigree; skewing; X Chromosome Inactivation - genetics; X-inactivation; Young Adult; Human; X-inactivation; Skin disease; Nervous system diseases; Metabolic diseases; Nervous system; Inactivation; Enzymopathy; Inorganic element; Fragment; junction fragment; Cerebral disorder; Genetic disease; Menkes disease; skewing; Genetic counseling; Central nervous system disease; Female; Genetics; Menkes syndrome; Junction; Carrier; Copper; ATP7A
• ISSN: 0009-9163; 1399-0004
• DOI: 10.1111/j.1399-0004.2010.01451.x

Desai V, Donsante A, Swoboda KJ, Martensen M, Thompson J, Kaler SG. 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.