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Vol. 113, No. 1-4, 2006
Issue release date: March 2006
Cytogenet Genome Res 113:292–299 (2006)
(DOI:10.1159/000090844)

Imprinting defects on human chromosome 15

Horsthemke B. · Buiting K.
Institut für Humangenetik, Universitätsklinikum Essen, Essen (Germany)

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Abstract

The Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are two distinct neurogenetic diseases that are caused by the loss of function of imprinted genes on the proximal long arm of human chromosome 15. In a few percent of patients with PWS and AS, the disease is due to aberrant imprinting and gene silencing. In patients with PWS and an imprinting defect, the paternal chromosome carries a maternal imprint. In patients with AS and an imprinting defect, the maternal chromosome carries a paternal imprint. Imprinting defects offer a unique opportunity to identify some of the factors and mechanisms involved in imprint erasure, resetting and maintenance. In approximately 10% of cases the imprinting defects are caused by a microdeletion affecting the 5′ end of the SNURF-SNRPN locus. These deletions define the 15q imprinting center (IC), which regulates imprinting in the whole domain. These findings have been confirmed and extended in knock-out and transgenic mice. In the majority of patients with an imprinting defect, the incorrect imprint has arisen without a DNA sequence change, possibly as the result of stochastic errors of the imprinting process or the effect of exogenous factors.



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References

  1. Bielinska B, Blaydes SM, Buiting K, Yang T, Krajewska-Walasek M, Horsthemke B, Brannan CI: De novo deletions of SNRPN exon 1 in early human and mouse embryos result in a paternal to maternal imprint switch. Nat Genet 25:74–78 (2000).
  2. Bourc’his D, Bestor TH: Meiotic catastrophe and retrotransposon reactivation in male germ cells lacking Dnmt3L. Nature 431:96–99 (2004).
  3. Bourc’his D, Xu GL, Lin CS, Bollman B, Bestor TH: Dnmt3L and the establishment of maternal genomic imprints. Science 294:2536–2539 (2001).
  4. Bressler J, Tsai TF, Wu MY, Tsai SF, Ramirez MA, Armstrong D, Beaudet AL: The SNRPN promoter is not required for genomic imprinting of the Prader-Willi/Angelman domain in mice. Nat Genet 28:232–240 (2001).
  5. Buiting K, Saitoh S, Gross S, Dittrich B, Schwartz S, Nicholls RD, Horsthemke B: Inherited microdeletions in the Angelman and Prader-Willi syndromes define an imprinting centre on human chromosome 15. Nat Genet 9:395–400 (1995).
  6. Buiting K, Dittrich B, Gross S, Lich C, Farber C, Buchholz T, Smith E, et al: Sporadic imprinting defects in Prader-Willi syndrome and Angelman syndrome: implications for imprint-switch models, genetic counseling, and prenatal diagnosis. Am J Hum Genet 63:170–180 (1998).
  7. Buiting K, Lich C, Cottrell S, Barnicoat A, Horsthemke B: A 5-kb imprinting center deletion in a family with Angelman syndrome reduces the shortest region of deletion overlap to 880 bp. Hum Genet 105:665–666 (1999).
  8. Buiting K, Barnicoat A, Lich C, Pembrey M, Malcolm S, Horsthemke B: Disruption of the bipartite imprinting center in a family with Angelman syndrome. Am J Hum Genet 68:1290–1294 (2001).
  9. Buiting K, Gross S, Lich C, Gillessen-Kaesbach G, el-Maarri O, Horsthemke B: Epimutations in Prader-Willi and Angelman syndromes: a molecular study of 136 patients with an imprinting defect. Am J Hum Genet 72:571–577 (2003).
  10. Castro R, Rivera I, Ravasco P, Camilo ME, Jakobs C, Blom HJ, de Almeida IT: 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C→T and 1298A→C mutations are associated with DNA hypomethylation. J Med Genet 41:454–458 (2004).
  11. Cavaillé J, Vitali P, Basyuk E, Huttenhofer A, Bachellerie JP: A novel brain-specific box C/D small nucleolar RNA processed from tandemly repeated introns of a noncoding RNA gene in rats. J Biol Chem 276:26374–26383 (2001).
  12. Chaddha V, Agarwal S, Phadke SR, Halder A: Low level of mosaicism in atypical Prader Willi syndrome: detection using fluorescent in situ hybridization. Indian Pediatr 40:166–168 (2003).

    External Resources

  13. Chang AS, Moley KH, Wangler M, Feinberg AP, Debaun MR: Association between Beckwith-Wiedemann syndrome and assisted reproductive technology: a case series of 19 patients. Fertil Steril 83:349–354 (2005).
  14. Chong S, Whitelaw E: Epigenetic germline inheritance. Curr Opin Genet Dev 14:692–696 (2004).
  15. Cox GF, Burger J, Lip V, Mau UA, Sperling K, Wu BL, Horsthemke B: Intracytoplasmic sperm injection may increase the risk of imprinting defects. Am J Hum Genet 71:162–164 (2002).
  16. Dittrich B, Buiting K, Korn B, Rickard S, Buxton J, Saitoh S, Nicholls RD, Poustka A, Winterpacht A, Zabel B, Horsthemke B: Imprint switching on human chromosome 15 may involve alternative transcripts of the SNRPN gene. Nat Genet 14:163–170 (1996).
  17. El-Maarri O, Buiting K, Peery EG, Kroisel PM, Balaban B, Wagner K, Urman B, Heyd J, Lich C, Brannan CI, Walter J, Horsthemke B: Maternal methylation imprints on human chromosome 15 are established during or after fertilization. Nat Genet 27:341–344 (2001).
  18. Friso S, Choi SW, Girelli D, Mason JB, Dolnikowski GG, Bagley PJ, Olivieri O, Jacques PF, Rosenberg IH, Corrocher R, Selhub J: A common mutation in the 5,10-methylenetetrahydrofolate reductase gene affects genomic DNA methylation through an interaction with folate status. Proc Natl Acad Sci USA 99:5606–5611 (2002).
  19. Garfinkel MD, Ruden DM: Chromatin effects in nutrition, cancer, and obesity. Nutrition 20:56–62 (2004).
  20. Gillessen-Kaesbach G, Demuth S, Thiele H, Theile U, Lich C, Horsthemke B: A previously unrecognised phenotype characterised by obesity, muscular hypotonia, and ability to speak in patients with Angelman syndrome caused by an imprinting defect. Eur J Hum Genet 7:638–644 (1999).
  21. Glenn CC, Nicholls RD, Robinson WP, Saitoh S, Niikawa N, Schinzel A, Horsthemke B, Driscoll DJ: Modification of 15q11→q13 DNA methylation imprints in unique Angelman and Prader-Willi patients. Hum Mol Genet 2:1377–1382 (1993).
  22. Gosden R, Trasler J, Lucifero D, Faddy M: Rare congenital disorders, imprinted genes, and assisted reproductive technology. Lancet 361:1975–1977 (2003).
  23. Horsthemke B, Ludwig M: Assisted reproduction – the epigenetic perspective. Hum Reprod Update 11:473–482 (2005).
  24. Horsthemke B, Lich C, Buiting K, Achmann R, Aulehla-Scholz C, Baumer A, et al: Problems in detecting mosaic DNA methylation in Angelman syndrome. Eur J Hum Genet 11:913–915 (2003a).
  25. Horsthemke B, Nazlican H, Husing J, Klein-Hitpass L, Claussen U, Michel S, Lich C, Gillessen-Kaesbach G, Buiting K: Somatic mosaicism for maternal uniparental disomy 15 in a girl with Prader-Willi syndrome: confirmation by cell cloning and identification of candidate downstream genes. Hum Mol Genet 12:2723–2732 (2003b).
  26. Howell CY, Bestor TH, Ding F, Latham KE, Mertineit C, Trasler JM, Chaillet JR: Genomic imprinting disrupted by a maternal effect mutation in the Dnmt1 gene. Cell 104:829–838 (2001).
  27. Huynh KD, Lee JT: Inheritance of a pre-inactivated paternal X chromosome in early mouse embryos. Nature 426:857–862 (2003).
  28. Ingrosso D, Cimmino A, Perna AF, Masella L, De Santo NG, De Bonis ML, et al: Folate treatment and unbalanced methylation and changes of allelic expression induced by hyperhomocysteinaemia in patients with uraemia. Lancet 361:1693–1699 (2003).
  29. Jaenisch R, Bird A: Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet 33 Suppl:245–254 (2003).
  30. Kantor B, Kaufman Y, Makedonski K, Razin A, Shemer R: Establishing the epigenetic status of the Prader-Willi/Angelman imprinting center in the gametes and embryo. Hum Mol Genet 13:2767–2779 (2004a).
  31. Kantor B, Makedonski K, Green-Finberg Y, Shemer R, Razin A: Control elements within the PWS/AS imprinting box and their function in the imprinting process. Hum Mol Genet 13:751–762 (2004b).
  32. Kearns M, Preis J, McDonald M, Morris C, Whitelaw E: Complex patterns of inheritance of an imprinted murine transgene suggest incomplete germline erasure. Nucleic Acids Res 28:3301–3309 (2000).
  33. Ludwig M, Katalinic A, Gross S, Sutcliffe A, Varon R, Horsthemke B: Increased prevalence of imprinting defects in patients with Angelman syndrome born to subfertile couples. J Med Genet 42:289–291 (2005).
  34. Mak W, Nesterova TB, de Napoles M, Appanah R, Yamanaka S, Otte AP, Brockdorff N: Reactivation of the paternal X chromosome in early mouse embryos. Science 303:666–669 (2004).
  35. Monk M: Mammalian embryonic development – insights from studies on the X chromosome. Cytogenet Genome Res 99:200–209 (2002).
  36. Morgan HD, Sutherland HG, Martin DI, Whitelaw E: Epigenetic inheritance at the agouti locus in the mouse. Nat Genet 23:314–318 (1999).
  37. Murrell A, Heeson S, Cooper WN, Douglas E, Apostolidou S, Moore GE, Maher ER, Reik W: An association between variants in the IGF2 gene and Beckwith-Wiedemann syndrome: interaction between genotype and epigenotype. Hum Mol Genet 13:247–255 (2004).
  38. Nazlican H, Zeschnigk M, Claussen U, Michel S, Boehringer S, Gillessen-Kaesbach G, Buiting K, Horsthemke B: Somatic mosaicism in patients with Angelman syndrome and an imprinting defect. Hum Mol Genet 13:2547–2555 (2004).
  39. Ohta T, Gray TA, Rogan PK, Buiting K, Gabriel JM, Saitoh S, et al: Imprinting-mutation mechanisms in Prader-Willi syndrome. Am J Hum Genet 64:397–413 (1999).
  40. Okamoto I, Otte AP, Allis CD, Reinberg D, Heard E: Epigenetic dynamics of imprinted X inactivation during early mouse development. Science 303:644–649 (2004).
  41. Orstavik KH, Eiklid K, van der Hagen CB, Spetalen S, Kierulf K, Skjeldal O, Buiting K: Another case of imprinting defect in a girl with Angelman syndrome who was conceived by intracytoplasmic semen injection. Am J Hum Genet 72:218–219 (2003).
  42. Paz MF, Avila S, Fraga MF, Pollan M, Capella G, Peinado MA, Sanchez-Cespedes M, Herman JG, Esteller M: Germ-line variants in methyl-group metabolism genes and susceptibility to DNA methylation in normal tissues and human primary tumors. Cancer Res 62:4519–4524 (2002).
  43. Perk J, Makedonski K, Lande L, Cedar H, Razin A, Shemer R: The imprinting mechanism of the Prader-Willi/Angelman regional control center. EMBO J 21:5807–5814 (2002).
  44. Reik W, Dean W, Walter J: Epigenetic reprogramming in mammalian development. Science 293:1089–1093 (2001).
  45. Rougeulle C, Cardoso C, Fontes M, Colleaux L, Lalande M: An imprinted antisense RNA overlaps UBE3A and a second maternally expressed transcript. Nat Genet 19:15–16 (1998).
  46. Runte M, Huttenhofer A, Gross S, Kiefmann M, Horsthemke B, Buiting K: The IC-SNURF- SNRPN transcript serves as a host for multiple small nucleolar RNA species and as an antisense RNA for UBE3A. Hum Mol Genet 10:2687–2700 (2001).
  47. Sandovici I, Leppert M, Hawk PR, Suarez A, Linares Y, Sapienza C: Familial aggregation of abnormal methylation of parental alleles at the IGF2/H19 and IGF2R differentially methylated regions. Hum Mol Genet 12:1569–1578 (2003).
  48. Schumacher A, Buiting K, Zeschnigk M, Doerfler W, Horsthemke B: Methylation analysis of the PWS/AS region does not support an enhancer-competition model. Nat Genet 19:324–325 (1998).
  49. Schweizer J, Zynger D, Francke U: In vivo nuclease hypersensitivity studies reveal multiple sites of parental origin-dependent differential chromatin conformation in the 150 kb SNRPN transcription unit. Hum Mol Genet 8:555–566 (1999).
  50. Shemer R, Hershko AY, Perk J, Mostoslavsky R, Tsuberi B, Cedar H, Buiting K, Razin A: The imprinting box of the Prader-Willi/Angelman syndrome domain. Nat Genet 26:440–443 (2000).
  51. Shi W, Haaf T: Aberrant methylation patterns at the two-cell stage as an indicator of early developmental failure. Mol Reprod Dev 63:329–334 (2002).
  52. Stern LL, Mason JB, Selhub J, Choi SW: Genomic DNA hypomethylation, a characteristic of most cancers, is present in peripheral leukocytes of individuals who are homozygous for the C677T polymorphism in the methylenetetrahydrofolate reductase gene. Cancer Epidemiol Biomarkers Prev 9:849–853 (2000).
  53. Sutcliffe JS, Nakao M, Christian S, Orstavik KH, Tommerup N, Ledbetter DH, Beaudet AL: Deletions of a differentially methylated CpG island at the SNRPN gene define a putative imprinting control region. Nat Genet 8:52–58 (1994).
  54. Wey E, Bartholdi D, Riegel M, Nazlican H, Horsthemke B, Schinzel A, Baumer A: Mosaic imprinting defect in a patient with an almost typical expression of the Prader-Willi syndrome. Eur J Hum Genet 13:273–277 (2005).
  55. Yang T, Adamson TE, Resnick JL, Leff S, Wevrick R, Francke U, Jenkins NA, Copeland NG, Brannan CI: A mouse model for Prader-Willi syndrome imprinting-centre mutations. Nat Genet 19:25–31 (1998).
  56. Zeschnigk M, Schmitz B, Dittrich B, Buiting K, Horsthemke B, Doerfler W: Imprinted segments in the human genome: different DNA methylation patterns in the Prader-Willi/Angelman syndrome region as determined by the genomic sequencing method. Hum Mol Genet 6:387–395 (1997).


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