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

ABSTRACT: 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.

SUBMITTER: Desai V

PROVIDER: S-EPMC3099248 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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

Desai V V Donsante A A Swoboda K J KJ Martensen M M Thompson J J Kaler S G SG

Clinical genetics 20110201 2

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 ...[more]

PMID: 20497190

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Project description:BackgroundX chromosome inactivation (XCI) is the mechanism by which the X-linked gene dosage is adjusted between the sexes. Evidence shows that many sex-specific diseases have their basis in X chromosome biology. While female schizophrenia patients often have a delayed age of disease onset and clinical phenotypes that are different from those of males, it is unknown whether the sex differences in schizophrenia are associated with X-linked gene dosage and the choice of X chromosome silencing in female cells. Previous studies demonstrated that sex chromosome aneuploidies may be related to the pathogeneses of some psychiatric diseases. Here, we examined the changes in skewed XCI in patients with schizophrenia.MethodsA total of 109 female schizophrenia (SCZ) patients and 80 age- and sex-matched healthy controls (CNTLs) were included in this study. We evaluated clinical features including disease onset age, disease duration, clinical symptoms by the Positive and Negative Syndrome Scale (PANSS) and antipsychotic treatment dosages. The XCI skewing patterns were analyzed by the methylation profile of the HUMARA gene found in DNA isolated from SCZ patient and CNTL leukocytes in the three age groups.ResultsFirst, we found that the frequency of skewed XCI in SCZ patients was 4 times more than that in the age- and sex-matched CNTLs (p < 0.01). Second, we found an earlier onset of severe XCI skewing in the SCZ patients than in CNTLs. Third, we demonstrated a close relationship between the severity of skewed XCI and schizophrenic symptoms (PANSS score ≥ 90) as well as the age of disease onset. Fourth, we demonstrated that the skewed XCI in SCZ patients was not transmitted from the patients' mothers.LimitationsThe XCI skewing pattern might differ depending on tissues or organs. Although this is the first study to explore skewed XCI in SCZ, in the future, samples from different tissues or cells in SCZ patients might be important for understanding the impact of skewed XCI in this disease.ConclusionOur study, for the first time, investigated skewed XCI in female SCZ patients and presented a potential mechanism for the sex differences in SCZ. Our data also suggested that XCI might be a potential target for the development of female-specific interventions for SCZ.

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

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

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