Rett syndrome (RTT) is a neurodevelopmental disorder that affects girls due primarily to heterozygous mutations in the X-linked gene encoding methyl-CpG binding protein 2 (MECP2). Random X-chromosome inactivation (XCI) results in cellular mosaicism in which some cells express wild-type (WT) MECP2 while other cells express mutant MECP2. The generation of patient-specific human induced pluripotent stem cells (hiPSCs) facilitates the production of RTT-hiPSC-derived neurons in vitro to investigate disease mechanisms and identify novel drug treatments. The generation of RTT-hiPSCs has been reported by many laboratories, however, the XCI status of RTT-hiPSCs has been inconsistent. Some report RTT-hiPSCs retain the inactive X-chromosome (post-XCI) of the founder somatic cell allowing isogenic RTT-hiPSCs that express only the WT or mutant MECP2 allele to be isolated from the same patient. Post-XCI RTT-hiPSCs-derived neurons retain this allele-specific expression pattern of WT or mutant MECP2. Conversely, others report RTT-hiPSCs in which the inactive X-chromosome of the founder somatic cell reactivates (pre-XCI) upon reprogramming into RTT-hiPSCs. Pre-XCI RTT-hiPSC-derived neurons exhibit random XCI resulting in cellular mosaicism with respect to WT and mutant MECP2 expression. Here we review and attempt to interpret the inconsistencies in XCI status of RTT-hiPSCs generated to date by comparison to other pluripotent systems in vitro and in vivo and the methods used to analyze XCI. Finally, we discuss the relative strengths and weaknesses of post- and pre-XCI hiPSCs in the context of RTT, and other X-linked and autosomal disorders for translational medicine.
Keywords: Rett syndrome, human induced pluripotent stem cells, X-chromosome inactivation
Citation: Cheung AYL, Horvath LM, Carrel L and Ellis J (2012) X-chromosome inactivation in Rett syndrome human induced pluripotent stem cells. Front. Psychiatry 3:24. doi: 10.3389/fpsyt.2012.00024
Received: 01 December 2011; Accepted: 05 March 2012;
Published online: 23 March 2012.
Edited by:Daniela Tropea, Trinity College Dublin, Ireland
Reviewed by:Ju Wang, University of Virginia, USA
Copyright: © 2012 Cheung, Horvath, Carrel and Ellis. This is an open-access article distributed under the terms of the Creative Commons Attribution Non Commercial License, which permits non-commercial use, distribution, and reproduction in other forums, provided the original authors and source are credited.
*Correspondence: James Ellis, Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto Medical Discovery Tower, 13-310, 101 College Street, Toronto, ON, Canada M5G 1L7. e-mail: firstname.lastname@example.org