IPSC Models of Chromosome 15Q Imprinting Disorders: From Disease Modeling to Therapeutic Strategies

  • Noelle D. Germain
  • Eric S. LevineEmail author
  • Stormy J. Chamberlain
Part of the Advances in Neurobiology book series (NEUROBIOL, volume 25)


The chromosome 15q11-q13 region of the human genome is regulated by genomic imprinting, an epigenetic phenomenon in which genes are expressed exclusively from one parental allele. Several genes within the 15q11-q13 region are expressed exclusively from the paternally inherited chromosome 15. At least one gene UBE3A, shows exclusive expression of the maternal allele, but this allele-specific expression is restricted to neurons. The appropriate regulation of imprinted gene expression across chromosome 15q11-q13 has important implications for human disease. Three different neurodevelopmental disorders result from aberrant expression of imprinted genes in this region: Prader–Willi syndrome (PWS), Angelman syndrome (AS), and 15q duplication syndrome.


Angelman syndrome Prader–Willi syndrome Dup15q syndrome Antisense oligonucleotides Genomic imprinting Chromosome 15q11-q13 UBE3A 



The work was supported by the following funding sources: NIH HD068730, NIH HD091823-01, Foundation for Prader–Willi Research, and Connecticut DPH Stem Cell Research Program (12SCBUCHC) to SJC, the Joseph Wagstaff Postdoctoral Fellowship to NDG, NIH MH094896 to ESL, and the Angelman Syndrome Foundation and Connecticut DPH Stem Cell Research Program (14-SCDIS) to both SJC and ESL.


  1. 1.
    Cassidy, S.B. and D.J. Driscoll, (2009). Prader-Willi syndrome. European Journal of Human Genetics, 17(1), 3–13.Google Scholar
  2. 2.
    Battaglia, A. (2005). The inv dup(15) or idic(15) syndrome: A clinically recognisable neurogenetic disorder. Brain Dev, 27(5), 365–369.Google Scholar
  3. 3.
    Christian, S.L., N.K. Bhatt, S.A. Martin, J.S. Sutcliffe, T. Kubota, B. Huang, et al., (1998). Integrated YAC contig map of the Prader-Willi/Angelman region on chromosome 15q11-q13 with average STS spacing of 35 kb. Genome Research, 8(2), 146–157.Google Scholar
  4. 4.
    Amos-Landgraf, J.M., Y. Ji, W. Gottlieb, T. Depinet, A.E. Wandstrat, S.B. Cassidy, et al., (1999). Chromosome breakage in the Prader-Willi and Angelman syndromes involves recombination between large, transcribed repeats at proximal and distal breakpoints. American Journal of Human Genetics, 65(2), 370–386.Google Scholar
  5. 5.
    Christian, S.L., J.A. Fantes, S.K. Mewborn, B. Huang, and D.H. Ledbetter (1999). Large genomic duplicons map to sites of instability in the Prader-Willi/Angelman syndrome chromosome region (15q11-q13). Human Molecular Genetics, 8(6), 1025–1037.Google Scholar
  6. 6.
    Wang, N.J., D. Liu, A.S. Parokonny, and N.C. Schanen (2004). High-resolution molecular characterization of 15q11-q13 rearrangements by array comparative genomic hybridization (array CGH) with detection of gene dosage. American Journal of Human Genetics, 75(2), 267–281.Google Scholar
  7. 7.
    Battaglia, A. (2008). The inv dup (15) or idic (15) syndrome (Tetrasomy 15q). Orphanet Journal of Rare Diseases, 3, 30.Google Scholar
  8. 8.
    Hogart, A., K.A. Patzel, and J.M. LaSalle, (2008). Gender influences monoallelic expression of ATP10A in human brain. Human Genetics, 124(3), 235–242.Google Scholar
  9. 9.
    Chai, J.H., D.P. Locke, J.M. Greally, J.H. Knoll, T. Ohta, J. Dunai, et al., (2003). Identification of four highly conserved genes between breakpoint hotspots BP1 and BP2 of the Prader-Willi/Angelman syndromes deletion region that have undergone evolutionary transposition mediated by flanking duplicons. American Journal of Human Genetics, 73(4), 898–925.Google Scholar
  10. 10.
    Ji, Y., E.E. Eichler, S. Schwartz, and R.D. Nicholls, (2000). Structure of chromosomal duplicons and their role in mediating human genomic disorders. Genome Research, 10(5), 597–610.Google Scholar
  11. 11.
    Sahoo, T., D. del Gaudio, J.R. German, M. Shinawi, S.U. Peters, R.E. Person, et al., (2008). Prader-Willi phenotype caused by paternal deficiency for the HBII-85 C/D box small nucleolar RNA cluster. Nature Genetics, 40(6), 719–721.Google Scholar
  12. 12.
    dde Smith, A.J., C. Purmann, R.G. Walters, R.J. Ellis, S.E. Holder, M.M. Van Haelst, et al., (2009). A deletion of the HBII-85 class of small nucleolar RNAs (snoRNAs) is associated with hyperphagia, obesity and hypogonadism. Human Molecular Genetics, 18(17), 3257–3265.Google Scholar
  13. 13.
    Yang, T., T.E. Adamson, J.L. Resnick, S. Leff, R. Wevrick, U. Francke, et al., (1998). A mouse model for Prader-Willi syndrome imprinting-Centre mutations. Nature Genetics, 19(1), 25–31.Google Scholar
  14. 14.
    Chamberlain, S.J., K.A. Johnstone, A.J. DuBose, T.A. Simon, M.S. Bartolomei, J.L. Resnick, et al., (2004). Evidence for genetic modifiers of postnatal lethality in PWS-IC deletion mice. Human Molecular Genetics, 13(23), 2971–2977.Google Scholar
  15. 15.
    Gabriel, J.M., M. Merchant, T. Ohta, Y. Ji, R.G. Caldwell, M.J. Ramsey, et al., (1999). A transgene insertion creating a heritable chromosome deletion mouse model of Prader-Willi and Angelman syndromes. Proceedings of the National Academy of Sciences of the United States of America, 96(16), 9258–9263.Google Scholar
  16. 16.
    Gerard, M., L. Hernandez, R. Wevrick, and C.L. Stewart, (1999). Disruption of the mouse necdin gene results in early post-natal lethality. Nature Genetics, 23(2), 199–202.Google Scholar
  17. 17.
    Muscatelli, F., D.N. Abrous, A. Massacrier, I. Boccaccio, M. Le Moal, P. Cau, et al., (2000). Disruption of the mouse Necdin gene results in hypothalamic and behavioral alterations reminiscent of the human Prader-Willi syndrome. Human Molecular Genetics, 9(20), 3101–3110.Google Scholar
  18. 18.
    Mercer, R.E. and R. Wevrick, (2009). Loss of magel2, a candidate gene for features of Prader-Willi syndrome, impairs reproductive function in mice. PLoS One, 4(1), e4291.Google Scholar
  19. 19.
    Bischof, J.M., C.L. Stewart, and R. Wevrick (2007). Inactivation of the mouse Magel2 gene results in growth abnormalities similar to Prader-Willi syndrome. Human Molecular Genetics, 16(22), 2713–2719.Google Scholar
  20. 20.
    Ding, F., H.H. Li, S. Zhang, N.M. Solomon, S.A. Camper, P. Cohen, et al., (2008). SnoRNA Snord116 (Pwcr1/MBII-85) deletion causes growth deficiency and hyperphagia in mice. PLoS One, 3(3), e1709.Google Scholar
  21. 21.
    Polex-Wolf, J., B.Y. Lam, R. Larder, J. Tadross, D. Rimmington, F. Bosch, et al., (2018). Hypothalamic loss of Snord116 recapitulates the hyperphagia of Prader-Willi syndrome. The Journal of Clinical Investigation, 128(3), 960–969.Google Scholar
  22. 22.
    Schaaf, C.P., M.L. Gonzalez-Garay, F. Xia, L. Potocki, K.W. Gripp, B. Zhang, et al., (2013). Truncating mutations of MAGEL2 cause Prader-Willi phenotypes and autism. Nature Genetics, 45(11), 1405–1408.Google Scholar
  23. 23.
    Fountain, M.D., E. Aten, M.T. Cho, J. Juusola, M.A. Walkiewicz, J.W. Ray, et al., (2017). The phenotypic spectrum of Schaaf-Yang syndrome: 18 new affected individuals from 14 families. Genetics in Medicine, 19(1), 45–52.Google Scholar
  24. 24.
    Fountain, M.D., H. Tao, C.A. Chen, J. Yin, and C.P. Schaaf, (2017). Magel2 knockout mice manifest altered social phenotypes and a deficit in preference for social novelty. Genes, Brain, and Behavior, 16(6), 592–600.Google Scholar
  25. 25.
    Kozlov, S.V., J.W. Bogenpohl, M.P. Howell, R. Wevrick, S. Panda, J.B. Hogenesch, et al., (2007). The imprinted gene Magel2 regulates normal circadian output. Nature Genetics, 39(10), 1266–1272.Google Scholar
  26. 26.
    Chamberlain, S.J., P.F. Chen, K.Y. Ng, F. Bourgois-Rocha, F. Lemtiri-Chlieh, E.S. Levine, et al., (2010). Induced pluripotent stem cell models of the genomic imprinting disorders Angelman and Prader-Willi syndromes. Proceedings of the National Academy of Sciences of the United States of America, 107(41), 17668–17673.Google Scholar
  27. 27.
    Yang, J., J. Cai, Y. Zhang, X. Wang, W. Li, J. Xu, et al., (2010). Induced pluripotent stem cells can be used to model the genomic imprinting disorder Prader-Willi syndrome. The Journal of Biological Chemistry, 285(51), 40303–40311.Google Scholar
  28. 28.
    Stelzer, Y., I. Sagi, O. Yanuka, R. Eiges, and N. Benvenisty, (2014). The noncoding RNA IPW regulates the imprinted DLK1-DIO3 locus in an induced pluripotent stem cell model of Prader-Willi syndrome. Nature Genetics, 46(6), 551–557.Google Scholar
  29. 29.
    Burnett, L.C., C.A. LeDuc, C.R. Sulsona, D. Paull, S. Eddiry, B. Levy, et al., (2016). Induced pluripotent stem cells (iPSC) created from skin fibroblasts of patients with Prader-Willi syndrome (PWS) retain the molecular signature of PWS. Stem Cell Research, 17(3), 526–530.Google Scholar
  30. 30.
    Okuno, H., K. Nakabayashi, K. Abe, T. Ando, T. Sanosaka, J. Kohyama, et al., (2017). Changeability of the fully methylated status of the 15q11.2 region in induced pluripotent stem cells derived from a patient with Prader-Willi syndrome. Congenit Anom (Kyoto), 57(4), 96–103.Google Scholar
  31. 31.
    Eldar-Geva, T., V. Gross-Tsur, H.J. Hirsch, G. Altarescu, R. Segal, S. Zeligson, et al., (2018). Incomplete methylation of a germ cell tumor (seminoma) in a Prader-Willi male. Molecular Genetics & Genomic Medicine, 6, 811.Google Scholar
  32. 32.
    Martins-Taylor, K., J.S. Hsiao, P.F. Chen, H. Glatt-Deeley, A.J. De Smith, A.I. Blakemore, et al., (2014). Imprinted expression of UBE3A in non-neuronal cells from a Prader-Willi syndrome patient with an atypical deletion. Human Molecular Genetics, 23(9), 2364–2373.Google Scholar
  33. 33.
    Langouet, M., H.R. Glatt-Deeley, M.S. Chung, C.M. Dupont-Thibert, E. Mathieux, E.C. Banda, et al., (2018). Zinc finger protein 274 regulates imprinted expression of transcripts in Prader-Willi syndrome neurons. Human Molecular Genetics, 27(3), 505–515.Google Scholar
  34. 34.
    Yamasaki, K., K. Joh, T. Ohta, H. Masuzaki, T. Ishimaru, T. Mukai, et al., (2003). Neurons but not glial cells show reciprocal imprinting of sense and antisense transcripts of Ube3a. Human Molecular Genetics, 12(8), 837–847.Google Scholar
  35. 35.
    Lossie, A.C., M.M. Whitney, D. Amidon, H.J. Dong, P. Chen, D. Theriaque, et al., (2001). Distinct phenotypes distinguish the molecular classes of Angelman syndrome. Journal of Medical Genetics, 38(12), 834–845.Google Scholar
  36. 36.
    Tan, W.H., L.M. Bird, R.L. Thibert, and C.A. Williams, (2014). If not Angelman, what is it? A review of Angelman-like syndromes. American Journal of Medical Genetics. Part A, 164A(4), 975–992.Google Scholar
  37. 37.
    Jiang, Y.H., D. Armstrong, U. Albrecht, C.M. Atkins, J.L. Noebels, G. Eichele, et al., (1998). Mutation of the Angelman ubiquitin ligase in mice causes increased cytoplasmic p53 and deficits of contextual learning and long-term potentiation. Neuron, 21(4), 799–811.Google Scholar
  38. 38.
    Miura, K., T. Kishino, E. Li, H. Webber, P. Dikkes, G.L. Holmes, et al., (2002). Neurobehavioral and electroencephalographic abnormalities in Ube3a maternal-deficient mice. Neurobiology of Disease, 9(2), 149–159.Google Scholar
  39. 39.
    Huang, H.S., A.J. Burns, R.J. Nonneman, L.K. Baker, N.V. Riddick, V.D. Nikolova, et al., (2013). Behavioral deficits in an Angelman syndrome model: Effects of genetic background and age. Behavioural Brain Research, 243, 79–90.Google Scholar
  40. 40.
    Silva-Santos, S., G.M. van Woerden, C.F. Bruinsma, E. Mientjes, M.A. Jolfaei, B. Distel, et al., (2015). Ube3a reinstatement identifies distinct developmental windows in a murine Angelman syndrome model. The Journal of Clinical Investigation, 125(5), 2069–2076.Google Scholar
  41. 41.
    Stanurova, J., A. Neureiter, M. Hiber, H. de Oliveira Kessler, K. Stolp, R. Goetzke, et al., (2016). Angelman syndrome-derived neurons display late onset of paternal UBE3A silencing. Scientific Reports, 6, 30792.Google Scholar
  42. 42.
    Takahashi, Y., J. Wu, K. Suzuki, P. Martinez-Redondo, M. Li, H.K. Liao, et al., (2017). Integration of CpG-free DNA induces de novo methylation of CpG islands in pluripotent stem cells. Science, 356(6337), 503–508.Google Scholar
  43. 43.
    Polvora-Brandao, D., M. Joaquim, I. Godinho, D. Aprile, A.R. Alvaro, I. Onofre, et al., (2018). Loss of hierarchical imprinting regulation at the Prader-Willi/Angelman syndrome locus in human iPSCs. Human Molecular Genetics, 27(23), 3999–4011.Google Scholar
  44. 44.
    Fink, J.J., Robinson, T.M., Germain, N.D., Sirois, C.L., Bolduc, K.A., Ward, A.J., Rigo, F., Chamberlain, S.J., and Levine, E.S., (2017). Disrupted neuronal maturation in Angelman syndrome-derived induced pluripotent stem cells. Nature Communications, 8, 15038.Google Scholar
  45. 45.
    Schroer, R.J., M.C. Phelan, R.C. Michaelis, E.C. Crawford, S.A. Skinner, M. Cuccaro, et al., (1998). Autism and maternally derived aberrations of chromosome 15q. American Journal of Medical Genetics, 76(4), 327–336.Google Scholar
  46. 46.
    Cook, E.H., Jr., R.Y. Courchesne, N.J. Cox, C. Lord, D. Gonen, S.J. Guter, et al., (1998). Linkage-disequilibrium mapping of autistic disorder, with 15q11-13 markers. American Journal of Human Genetics, 62(5), 1077–1083.Google Scholar
  47. 47.
    Cook, E.H., Jr., V. Lindgren, B.L. Leventhal, R. Courchesne, A. Lincoln, C. Shulman, et al., (1997). Autism or atypical autism in maternally but not paternally derived proximal 15q duplication. American Journal of Human Genetics, 60(4), 928–934.Google Scholar
  48. 48.
    Reiter, L., Cleary, J., Brewer, V., Jabbour, J.T., Schanen, N.C., and Urraca, N., (2009). Maternal, but not paternal, interstitial duplications of chromosome 15q11.2-q13 are associated with ASD in 7 individuals. In Presented at the 59th annual meeting of the American society for human genetics, October 23, 2009, Honolulu, Hawaii.Google Scholar
  49. 49.
    Mohandas, T.K., J.P. Park, R.A. Spellman, J.J. Filiano, A.C. Mamourian, A.B. Hawk, et al., (1999). Paternally derived de novo interstitial duplication of proximal 15q in a patient with developmental delay. American Journal of Medical Genetics, 82(4), 294–300.Google Scholar
  50. 50.
    Marshall, C.R., A. Noor, J.B. Vincent, A.C. Lionel, L. Feuk, J. Skaug, et al., (2008). Structural variation of chromosomes in autism spectrum disorder. American Journal of Human Genetics, 82(2), 477–488.Google Scholar
  51. 51.
    Szatmari, P., A.D. Paterson, L. Zwaigenbaum, W. Roberts, J. Brian, X.Q. Liu, et al., (2007). Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nature Genetics, 39(3), 319–328.Google Scholar
  52. 52.
    Nakatani, J., K. Tamada, F. Hatanaka, S. Ise, H. Ohta, K. Inoue, et al., (2009). Abnormal behavior in a chromosome-engineered mouse model for human 15q11-13 duplication seen in autism. Cell, 137(7), 1235–1246.Google Scholar
  53. 53.
    Germain ND, C.P., Plocik AM, Glatt-Deeley H, Brown J, Fink JJ, Bolduc KA, Robinson TM, Levine ES, Reiter LT, Graveley BR, Lalande M, Chamberlain SJ., (2014). Gene expression analysis of human induced pluripotent stem cell-derived neurons carrying copy number variants of chromosome 15q11-q13.1. Molecular Autism, 5, 44.Google Scholar
  54. 54.
    Brannan, C.I. and M.S. Bartolomei, (1999). Mechanisms of genomic imprinting. Current Opinion in Genetics & Development, 9(2), 164–170.Google Scholar
  55. 55.
    Johnstone, K.A., A.J. DuBose, C.R. Futtner, M.D. Elmore, C.I. Brannan, and J.L. Resnick, (2006). A human imprinting Centre demonstrates conserved acquisition but diverged maintenance of imprinting in a mouse model for Angelman syndrome imprinting defects. Human Molecular Genetics, 15(3), 393–404.Google Scholar
  56. 56.
    Schumacher, A. and W. Doerfler, (2004). Influence of in vitro manipulation on the stability of methylation patterns in the Snurf/Snrpn-imprinting region in mouse embryonic stem cells. Nucleic Acids Research, 32(4), 1566–1576.Google Scholar
  57. 57.
    Kim, K.P., A. Thurston, C. Mummery, D. Ward-van Oostwaard, H. Priddle, C. Allegrucci, et al., (2007). Gene-specific vulnerability to imprinting variability in human embryonic stem cell lines. Genome Research, 17(12), 1731–1742.Google Scholar
  58. 58.
    Rugg-Gunn, P.J., A.C. Ferguson-Smith, and R.A. Pedersen, (2007). Status of genomic imprinting in human embryonic stem cells as revealed by a large cohort of independently derived and maintained lines. Human Molecular Genetics, 16(2), R243–R251.Google Scholar
  59. 59.
    Stadtfeld, M., E. Apostolou, H. Akutsu, A. Fukuda, P. Follett, S. Natesan, et al., (2010). Aberrant silencing of imprinted genes on chromosome 12qF1 in mouse induced pluripotent stem cells. Nature, 465(7295), 175–181.Google Scholar
  60. 60.
    Inoue, K., T. Kohda, J. Lee, N. Ogonuki, K. Mochida, Y. Noguchi, et al., (2002). Faithful expression of imprinted genes in cloned mice. Science, 295(5553), 297.Google Scholar
  61. 61.
    Ohta, T., T.A. Gray, P.K. Rogan, K. Buiting, J.M. Gabriel, S. Saitoh, et al., (1999). Imprinting-mutation mechanisms in Prader-Willi syndrome. American Journal of Human Genetics, 64(2), 397–413.Google Scholar
  62. 62.
    Saitoh, S., K. Buiting, P.K. Rogan, J.L. Buxton, D.J. Driscoll, J. Arnemann, et al., (1996). Minimal definition of the imprinting center and fixation of chromosome 15q11-q13 epigenotype by imprinting mutations. Proceedings of the National Academy of Sciences of the United States of America, 93(15), 7811–7815.Google Scholar
  63. 63.
    Buiting, K., C. Lich, S. Cottrell, A. Barnicoat, and B. Horsthemke, (1999). A 5-kb imprinting center deletion in a family with Angelman syndrome reduces the shortest region of deletion overlap to 880 bp. Human Genetics, 105(6), 665–666.Google Scholar
  64. 64.
    Peery, E.G., M.D. Elmore, J.L. Resnick, C.I. Brannan, and K.A. Johnstone, (2007). A targeted deletion upstream of Snrpn does not result in an imprinting defect. Mammalian Genome, 18(4), 255–262.Google Scholar
  65. 65.
    Smith, E.Y., C.R. Futtner, S.J. Chamberlain, K.A. Johnstone, and J.L. Resnick, (2011). Transcription is required to establish maternal imprinting at the Prader-Willi syndrome and Angelman syndrome locus. PLoS Genetics, 7(12), e1002422.Google Scholar
  66. 66.
    El-Maarri, O., K. Buiting, E.G. Peery, P.M. Kroisel, B. Balaban, K. Wagner, et al., (2001). Maternal methylation imprints on human chromosome 15 are established during or after fertilization. Nature Genetics, 27(3), 341–344.Google Scholar
  67. 67.
    Fink, J.J., T.M. Robinson, N.D. Germain, C.L. Sirois, K.A. Bolduc, A.J. Ward, et al., (2017). Disrupted neuronal maturation in Angelman syndrome-derived induced pluripotent stem cells. Nature Communications, 8, 15038.Google Scholar
  68. 68.
    Kaphzan, H., S.A. Buffington, J.I. Jung, M.N. Rasband, and E. Klann, (2011). Alterations in intrinsic membrane properties and the axon initial segment in a mouse model of Angelman syndrome. The Journal of Neuroscience, 31(48), 17637–17648.Google Scholar
  69. 69.
    Otmakhov, N., L. Khibnik, N. Otmakhova, S. Carpenter, S. Riahi, B. Asrican, et al., (2004). Forskolin-induced LTP in the CA1 hippocampal region is NMDA receptor dependent. Journal of Neurophysiology, 91(5), 1955–1962.Google Scholar
  70. 70.
    Fink, J.J., J.D. Schreiner, J.E. Bloom, D.S. Baker, T.M. Robinson, R. Lieberman, et al., (2018). Hyperexcitable phenotypes in iPSC-derived neurons from patients with 15q11-q13 duplication syndrome, a genetic form of autism. BioRxiv. [Preprint]. Retrieved from
  71. 71.
    Wang, L., K. Meece, D.J. Williams, K.A. Lo, M. Zimmer, G. Heinrich, et al., (2015). Differentiation of hypothalamic-like neurons from human pluripotent stem cells. The Journal of Clinical Investigation, 125(2), 796–808.Google Scholar
  72. 72.
    Rajamani, U., A.R. Gross, B.E. Hjelm, A. Sequeira, M.P. Vawter, J. Tang, et al., (2018). Super-obese patient-derived iPSC hypothalamic neurons exhibit obesogenic signatures and hormone responses. Cell Stem Cell, 22(5), 698–712. e9.Google Scholar
  73. 73.
    Rougeulle, C., H. Glatt, and M. Lalande, (1997). The Angelman syndrome candidate gene, UBE3A/E6-AP, is imprinted in brain. Nature Genetics, 17(1), 14–15.Google Scholar
  74. 74.
    Chamberlain, S.J. and C.I. Brannan, (2001). The Prader-Willi syndrome imprinting center activates the paternally expressed murine Ube3a antisense transcript but represses paternal Ube3a. Genomics, 73(3), 316–322.Google Scholar
  75. 75.
    Meng, L., R.E. Person, and A.L. Beaudet, (2012). Ube3a-ATS is an atypical RNA polymerase II transcript that represses the paternal expression of Ube3a. Human Molecular Genetics, 21(13), 3001–3012.Google Scholar
  76. 76.
    Meng, L., R.E. Person, W. Huang, P.J. Zhu, M. Costa-Mattioli, and A.L. Beaudet, (2013). Truncation of Ube3a-ATS Unsilences paternal Ube3a and ameliorates behavioral defects in the Angelman syndrome mouse model. PLoS Genetics, 9(12), e1004039.Google Scholar
  77. 77.
    Hsiao, J.S., N.D. Germain, A. Wilderman, C. Stoddard, L.A. Wojenski, G.J. Villafano, et al., (2019). A bipartite boundary element restricts UBE3A imprinting to mature neurons. Proceedings of the National Academy of Sciences of the United States of America, 116(6), 2181–2186.Google Scholar
  78. 78.
    Huang, H.S., J.A. Allen, A.M. Mabb, I.F. King, J. Miriyala, B. Taylor-Blake, et al., (2012). Topoisomerase inhibitors unsilence the dormant allele of Ube3a in neurons. Nature, 481(7380), 185–189.Google Scholar
  79. 79.
    Lee, H.M., E.P. Clark, M.B. Kuijer, M. Cushman, Y. Pommier, and B.D. Philpot, (2018). Characterization and structure-activity relationships of indenoisoquinoline-derived topoisomerase I inhibitors in unsilencing the dormant Ube3a gene associated with Angelman syndrome. Molecular Autism, 9, 45.Google Scholar
  80. 80.
    Mabb, A.M., J.M. Simon, I.F. King, H.M. Lee, L.K. An, B.D. Philpot, et al., (2016). Topoisomerase 1 regulates gene expression in neurons through cleavage complex-dependent and -independent mechanisms. PLoS One, 11(5), e0156439.Google Scholar
  81. 81.
    King, I.F., C.N. Yandava, A.M. Mabb, J.S. Hsiao, H.S. Huang, B.L. Pearson, et al., (2013). Topoisomerases facilitate transcription of long genes linked to autism. Nature, 501(7465), 58–62.Google Scholar
  82. 82.
    Mabb, A.M., P.H. Kullmann, M.A. Twomey, J. Miriyala, B.D. Philpot, and M.J. Zylka, (2014). Topoisomerase 1 inhibition reversibly impairs synaptic function. Proceedings of the National Academy of Sciences of the United States of America, 111(48), 17290–17295.Google Scholar
  83. 83.
    Watts, J.K. and D.R. Corey, (2012). Silencing disease genes in the laboratory and the clinic. The Journal of Pathology, 226(2), 365–379.Google Scholar
  84. 84.
    Geary, R.S., D. Norris, R. Yu, and C.F. Bennett, (2015). Pharmacokinetics, biodistribution and cell uptake of antisense oligonucleotides. Advanced Drug Delivery Reviews, 87, 46–51.Google Scholar
  85. 85.
    Beaudet, A.L. and L. Meng, (2016). Gene-targeting pharmaceuticals for single-gene disorders. Human Molecular Genetics, 25(R1), R18–R26.Google Scholar
  86. 86.
    Meng, L., A.J. Ward, S. Chun, C.F. Bennett, A.L. Beaudet, and F. Rigo, (2015). Towards a therapy for Angelman syndrome by targeting a long non-coding RNA. Nature, 518(7539), 409–412.Google Scholar
  87. 87.
    Hori, S., T. Yamamoto, and S. Obika, XRN2 (2015). XRN2 is required for the degradation of target RNAs by RNase H1-dependent antisense oligonucleotides. Biochemical and Biophysical Research Communications, 464(2), 506–511.Google Scholar
  88. 88.
    Lima, W.F., C.L. De Hoyos, X.H. Liang, and S.T. Crooke, (2016). RNA cleavage products generated by antisense oligonucleotides and siRNAs are processed by the RNA surveillance machinery. Nucleic Acids Research, 44(7), 3351–3363.Google Scholar
  89. 89.
    West, S., N. Gromak, and N.J. Proudfoot, (2004). Human 5′ --> 3′ exonuclease Xrn2 promotes transcription termination at co-transcriptional cleavage sites. Nature, 432(7016), 522–525.Google Scholar
  90. 90.
    Smith, S.E., Y.D. Zhou, G. Zhang, Z. Jin, D.C. Stoppel, and M.P. Anderson, (2011). Increased gene dosage of Ube3a results in autism traits and decreased glutamate synaptic transmission in mice. Science Translational Medicine, 3(103), 103ra97.Google Scholar
  91. 91.
    Urraca, N., J. Cleary, V. Brewer, E.K. Pivnick, K. McVicar, R.L. Thibert, et al., (2013). The Interstitial Duplication 15q11.2-q13 Syndrome Includes Autism, Mild Facial Anomalies and a Characteristic EEG Signature. Autism Research, 6(4), 268–279.Google Scholar
  92. 92.
    Napoli, I., V. Mercaldo, P.P. Boyl, B. Eleuteri, F. Zalfa, S. De Rubeis, et al., (2008). The fragile X syndrome protein represses activity-dependent translation through CYFIP1, a new 4E-BP. Cell, 134(6), 1042–1054.Google Scholar
  93. 93.
    Murphy, S.M., A.M. Preble, U.K. Patel, K.L. O’Connell, D.P. Dias, M. Moritz, et al., (2001). GCP5 and GCP6: Two new members of the human gamma-tubulin complex. Molecular Biology of the Cell, 12(11), 3340–3352.Google Scholar
  94. 94.
    Kuhnle, S., U. Kogel, S. Glockzin, A. Marquardt, A. Ciechanover, K. Matentzoglu, et al., (2011). Physical and functional interaction of the HECT ubiquitin-protein ligases E6AP and HERC2. The Journal of Biological Chemistry, 286(22), 19410–19416.Google Scholar
  95. 95.
    Martinez-Noel, G., J.T. Galligan, M.E. Sowa, V. Arndt, T.M. Overton, J.W. Harper, et al., (2012). Identification and proteomic analysis of distinct UBE3A/E6AP protein complexes. Molecular and Cellular Biology, 32(15), 3095–3106.Google Scholar
  96. 96.
    Svenstrup, K., R.S. Moller, J. Christensen, E. Budtz-Jorgensen, M. Gilling, and J.E. Nielsen, (2011). NIPA1 mutation in complex hereditary spastic paraplegia with epilepsy. European Journal of Neurology, 18(9), 1197–1199.Google Scholar
  97. 97.
    Goytain, A., R.M. Hines, A. El-Husseini, and G.A. Quamme, (2007). NIPA1(SPG6), the basis for autosomal dominant form of hereditary spastic paraplegia, encodes a functional Mg2+ transporter. The Journal of Biological Chemistry, 282(11), 8060–8068.Google Scholar
  98. 98.
    Cruvinel, E., T. Budinetz, N. Germain, S. Chamberlain, M. Lalande, and K. Martins-Taylor, (2014). Reactivation of maternal SNORD116 cluster via SETDB1 knockdown in Prader-Willi syndrome iPSCs. Human Molecular Genetics, 23(17), 4674–4685.Google Scholar
  99. 99.
    Xin, Z., M. Tachibana, M. Guggiari, E. Heard, Y. Shinkai, and J. Wagstaff, (2003). Role of histone methyltransferase G9a in CpG methylation of the Prader-Willi syndrome imprinting center. The Journal of Biological Chemistry, 278(17), 14996–15000.Google Scholar
  100. 100.
    Kim, Y., H.M. Lee, Y. Xiong, N. Sciaky, S.W. Hulbert, X. Cao, et al., (2017). Targeting the histone methyltransferase G9a activates imprinted genes and improves survival of a mouse model of Prader-Willi syndrome. Nature Medicine, 23(2), 213–222.Google Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  • Noelle D. Germain
    • 1
  • Eric S. Levine
    • 2
    Email author
  • Stormy J. Chamberlain
    • 1
  1. 1.Department of Genetics and Genome SciencesUniversity of Connecticut School of MedicineFarmingtonUSA
  2. 2.Department of NeuroscienceUniversity of Connecticut School of MedicineFarmingtonUSA

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