Induced pluripotent stem cell models of the genomic imprinting disorders Angelman and Prader-Willi syndromes.
Angelman syndrome (AS) and Prader-Willi syndrome (PWS) are neurodevelopmental disorders of genomic imprinting. AS results from loss of function of the ubiquitin protein ligase E3A (UBE3A) gene, whereas the genetic defect in PWS is unknown. Although induced pluripotent stem cells (iPSCs) provide invaluable models of human disease, nuclear reprogramming could limit the usefulness of iPSCs from patients who have AS and PWS should the genomic imprint marks be disturbed by the epigenetic reprogramming process. Our iPSCs derived from patients with AS and PWS show no evidence of DNA methylation imprint erasure at the cis-acting PSW imprinting center. Importantly, we find that, as in normal brain, imprinting of UBE3A is established during neuronal differentiation of AS iPSCs, with the paternal UBE3A allele repressed concomitant with up-regulation of the UBE3A antisense transcript. These iPSC models of genomic imprinting disorders will facilitate investigation of the AS and PWS disease processes and allow study of the developmental timing and mechanism of UBE3A repression in human neurons.
Chamberlain
Stormy J
SJ
University of Connecticut Stem Cell Institute and Departments of Genetics and Developmental Biology and Neuroscience, University of Connecticut Health Center, Farmington, CT 06030, USA. chamberlain@uchc.edu
Chen
Pin-Fang
PF
Ng
Khong Y
KY
Bourgois-Rocha
Fany
F
Lemtiri-Chlieh
Fouad
F
Levine
Eric S
ES
Lalande
Marc
M
D017204:Angelman Syndrome / Q000235:genetics*; D002454:Cell Differentiation / Q000502:physiology*; D017931:DNA Primers / Q000235:genetics; D004594:Electrophysiology; D018392:Genomic Imprinting / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D008954:Models, Biological; D009474:Neurons / Q000502:physiology; D039904:Pluripotent Stem Cells / Q000502:physiology*; D016133:Polymerase Chain Reaction; D011218:Prader-Willi Syndrome / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics
D017931:DNA Primers; C471639:UBE3A protein, human; D044767:Ubiquitin-Protein Ligases