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Genomisches Imprinting und Imprintingfehler

Genomic imprinting and imprinting defects

Zusammenfassung

Genomisches Imprinting ist ein epigenetischer Prozess, bei dem die männliche und die weibliche Keimbahn bestimmte Genregionen durch Histonmodifikationen und DNA-Methylierung so prägen, dass nur das väterliche oder nur das mütterliche Allel eines Gens aktiv ist. Genomische Imprints werden in primordialen Keimzellen gelöscht, während späterer Phasen der Keimzellentwicklung neu etabliert und bei den somatischen Zellteilungen während der postzygotischen Entwicklung stabil weitergegeben. Fehler in der Entfernung der Imprints, ihrer Etablierung oder ihrer Erhaltung führen zu falschen epigenetischen Mustern und Expressionsprofilen, die spezifische Erkrankungen verursachen können. Imprintingfehler können spontan, ohne jegliche Änderungen in der DNA-Sequenz, auftreten (primäre Imprintingfehler) oder als Folge einer Mutation in einem cis -regulatorischen Element oder einem trans -aktiven Faktor (sekundäre Imprintingfehler). Die Unterscheidung zwischen primären und sekundären Imprintingfehlern ist für die Abschätzung des Wiederholungsrisikos in betroffenen Familien wesentlich.

Abstract

Genomic imprinting is an epigenetic process by which specific gene regions are marked by the male and the female germ lines by histone modifications and DNA methylation, so that only the paternal allele or only the maternal allele of a gene is active. Genomic imprints are erased in primordial germ cells, newly established during later stages of germ cell development and stably inherited through somatic cell divisions during postzygotic development. Defects in imprint erasure, establishment or maintenance result in aberrant epigenetic patterns and expression profiles and can cause specific diseases. Imprinting defects can occur spontaneously without any DNA sequence change (primary imprinting defect) or as the result of a mutation in a cis-regulatory element or a trans-acting factor (secondary imprinting defect). The distinction between primary and secondary imprinting defects is important for assessing the risk of recurrence in affected families.

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Literatur

  1. 1.

    Reik W, Walter J (2001) Genomic imprinting: parental influence on the genome. Nat Rev Genet 2:21–32

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Buiting K, Saitoh S, Gross S et al (1995) Inherited microdeletions in the Angelman and Prader-Willi syndromes define an imprinting centre on human chromosome 15. Nat Genet 9:395–400

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Wilkins JF, Haig D (2003) What good is genomic imprinting: the function of parent-specific gene expression. Nat Rev Genet 45:359–368

    Article  Google Scholar 

  4. 4.

    McGrath J, Solter D (1984) Completion of mouse embryogenesis requires both the maternal and paternal genomes. Cell 37:179–183

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Surani MA, Barton SC, Norris ML (1984) Development of reconstituted mouse eggs suggests imprinting of the genome during gametogenesis. Nature 308:548–550

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Engel E (1980) A new genetic concept: uniparental disomy and its potential effect, isodisomy. Am J Med Genet 6:137–143

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Nakamura T, Arai Y, Umehara H et al (2007) PGC7/Stella protects against DNA demethylation in early embryogenesis. Nat Cell Biol 9:64–71

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Ooi SK, Bestor TH (2008) The colorful history of active DNA demethylation. Cell 27:1145–1148

    Article  Google Scholar 

  9. 9.

    Kaneda M, Okano M, Hata K et al (2004) Essential role for de novo DNA methyltransferases Dnmt3a in paternal and maternal imprinting. Nature 429:900–903

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Ciccone DN, Su H, Hevi S et al (2009) KDM1B is a histone H3K4 demethylase required to establish maternal genomic imprints. Nature 461:415–418

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Li X, Ito M, Zhou F et al (2008) A maternal-zygotic effect gene, Zfp57, maintains both maternal and paternal imprints. Dev Cell 15:547–557

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Dittrich B, Buiting K, Korn B et al (1996) Imprint switching on human chromosome 15 may involve alternative transcripts of the SNRPN gene. Nat Genet 14:163–170

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Chotalia M, Smallwood SA, Ruf N et al (2009) Transcription is required for establishment of germline methylation marks at imprinted genes. Genes Dev 23:105–117

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Glenn C, Nicholls R, Robinson W et al (1993) Modification of 15q11-q13 DNA methylation imprints in unique Angelman and Prader-Willi syndrome patients. Hum Mol Genet 2:1377–1382

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Reis A, Dittrich B, Greger V et al (1994) Imprinting mutations suggested by abnormal DNA methylation patterns in familial Angelman and Prader-Willi syndromes. Am J Hum Genet 54:741–747

    CAS  PubMed  Google Scholar 

  16. 16.

    Poplinski A, Tüttelmann F, Kanber D et al (2009) Idiopathic male infertility is strongly associated with aberrant methylationof MEST and IGF2/H19. Int J Androl 33:642–649

    Google Scholar 

  17. 17.

    Nazlican H, Zeschnigk M, Claussen U et al (2004) Somatic mosaicism in patients with Angelman syndrome and an imprinting defect. Hum Mol Genet 13:2547–2555

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Horsthemke B (2006) Epimutations in human disease. Curr Top Microbiol Immunol 310:45–59

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Murrell A, Heeson S, Cooper WN et al (2004) An association between variants in the IGF2 gene and Beckwith-Wiedemann syndrome: interaction between genotype and epigenotype. Hum Mol Genet 13:247–255

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Zogel C, Böhringer S, Groß S et al (2006) Identification of cis- and trans-acting factors possibly modifying the risk of epimutations on chromosome 15. Eur J Hum Genet 14:752–758

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Kaufman Y, Heled M, Perk J et al (2009) Protein-binding elements establish in the oocyte the primary imprint of the Prader-Willi/Angelman syndromes domain. Proc Natl Acad Sci U S A 106:10242–10247

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Friso S, Choi SW, Girelli D et al (2002) A common mutation in the 5,10-methylenetetrahydrofolate reductase gene affects genomic DNA methylation through an interaction with folate status. Proc Natl Acad Sci U S A 99:5606–5611

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Halliday J, Oke K, Breheny S et al (2004) Beckwith-Wiedemann syndrome and IVF: a case-control study. Am J Hum Genet 75:526–528

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Ludwig M, Katalinic A, Groß S et al (2005) Increased prevalence of imprinting defects in patients with Angelman syndrome born to subfertile couples. J Med Genet 42:289–291

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Buiting K, Gross S, Lich C et al (2003) Epimutations in Prader-Willi and Angelman syndromes: a molecular study of 136 patients with an imprinting defect. Am J Hum Genet 72:571–577

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Demars J, Shmela ME, Rossignol S et al (2010) Analysis of the IGF2/H19 imprinting control region uncovers new genetic defects, including mutations of OCT-binding sequences, in patients with 11p15 fetal growth disorders. Hum Mol Genet 19:803–814

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Judson H, Hayward BE, Sheridan E, Bonthron DT (2002) A global disorder of imprinting in the human female germ line. Nature 416:539–542

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Meyer E, Lim D, Pasha S et al (2009) Germline mutation in NLRP2 (NALP2) in a familial imprinting disorder (Beckwith-Wiedemann syndrome). PLoS Genet 5:e1000423

    Article  PubMed  Google Scholar 

  29. 29.

    Mackay DJ, Callaway JL, Marks SM et al (2008) Hypomethylation of multiple imprinted loci in individuals with transient neonatal diabetes is associated with mutations in ZFP57. Nat Genet 40:949–951

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    LaSalle JM (2007) The Odyssey of MeCP2 and parental imprinting. Epigenetics 2:5–10

    Article  Google Scholar 

  31. 31.

    Buiting K, Kanber D, Martín-Subero JI et al. (2008) Clinical features of maternal uniparental disomy 14 in patients with an epimutation and a deletion of the imprinted DLK1/GTL2 gene cluster. Hum Mutat 29:1141–1146

    CAS  Article  PubMed  Google Scholar 

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Danksagung

Der Autor dankt Dr. Gabriele Prescher für Hilfe bei der Abfassung des Manuskripts und dem BMBF für die Förderung des Netzwerks „Imprintingerkrankungen“ (01GM0882-886).

Interessenkonflikt

Der korrespondierende Autor gibt an, dass kein Interessenkonflikt besteht.

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Correspondence to B. Horsthemke.

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Horsthemke, B. Genomisches Imprinting und Imprintingfehler. medgen 22, 385–391 (2010). https://doi.org/10.1007/s11825-010-0244-x

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Schlüsselwörter

  • Epigenetischer Prozess
  • Genexpressionsregulierung
  • Genexpressionsprofile
  • Genetisches Imprinting
  • DNA-Methylierung

Keywords

  • Epigenetic process
  • Gene expression regulation
  • Gene expression profiles
  • Genomic imprinting
  • DNA methylation