Human Molecular Genetics Advance Access originally published online on May 11, 2005
Human Molecular Genetics 2005 14(13):1851-1861; doi:10.1093/hmg/ddi191
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Reduced proportion of Purkinje cells expressing paternally derived mutant Mecp2308 allele in female mouse cerebellum is not due to a skewed primary pattern of X-chromosome inactivation
1Embryology Unit, Children's Medical Research Institute, NSW, Australia, 2Discipline of Pediatrics and Child Health, University of Sydney, NSW, Australia, 3Western Sydney Genetics Program, Children's Hospital at Westmead, NSW, Australia and 4Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
* To whom correspondence should be addressed at: Embryology Unit, Children's Medical Research Institute, Locked Bag 23, Wentworthville, NSW 2145, Australia. Email: ptam{at}cmri.usyd.edu.au
Received March 24, 2005; Revised April 29, 2005; Accepted May 6, 2005
Rett syndrome (RTT) is an X-linked disorder caused by mutations in the methyl CpG binding protein 2 (MECP2) gene. The pattern of X-chromosome inactivation (XCI) is thought to play a role in phenotypic severity. In the present study, patterns of XCI were assessed by lacZ staining of embryos and adult brains of mice heterozygous for a X-linked Hmgcr–nls–lacZ transgene on a mutant mouse model of RTT. We found that there was no difference between the lacZ staining patterns in the brain of wild-type and heterozygous mutant embryos at embryonic day 9.5 (E9.5) suggesting that Mecp2 has no effect on the primary pattern of XCI. At 20 weeks of age, there was no significant difference between XCI patterns in the Purkinje cells in the cerebellum of heterozygous mutant and wild-type mice when the mutant allele was inherited from the mother. However, when the mutant allele was paternally inherited, a significant difference was detected. Thus, parental origin of the mutation may have a bearing on phenotype through XCI patterns. An estimation of the Purkinje cell precursor number based on XCI mosaicism revealed that, when the mutation was paternally inherited, the precursor number was less than that in the wild-type mice. Therefore, it is likely that the number of precursor cells allocated to the Purkinje cell lineage is affected by a paternally inherited mutation in Mecp2. We also observed that the pattern of XCI in cultured fibroblasts was significantly correlated with patterns in the Purkinje cells in mutant animals but not in wild-type mice.
Present address: Department of Biological Chemistry, University of California, Los Angeles, CA 90095, USA.
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