Skip to main content

Molekulargenetische Diagnostik von Imprintingerkrankungen

Relevanz von Multilocusmethylierungsdefekten

Molecular diagnosis of imprinting disorders

Relevance of multilocus methylation defects

Zusammenfassung

Bei allen derzeit bekannten Imprintingerkrankungen wurde über eine Assoziation mit molekularen Veränderungen an krankheitsspezifischen chromosomalen Loci berichtet. Die locusspezifische Zuordnung einiger dieser Krankheitsbilder wird erschwert durch den Nachweis so genannter Multilocusmethylierungsdefekte (MLMD): Dabei besteht nicht nur an krankheitsspezifischen geprägten Genorten eine aberrante Methylierung, sondern auch an anderen Loci. Klinisch zeigt sich mehrheitlich die Symptomatik nur einer Imprintingerkrankung, in einzelnen Fällen überlappen sich jedoch verschiedene Krankheitsbilder. Umgekehrt wurden auch Fälle mit gleichartigem MLMD-Muster, aber unterschiedlichen Krankheitsbildern beschrieben. Zur Abklärung von MLMD sollten daher Testverfahren eingesetzt werden, die auf Methylierungsveränderungen an verschiedenen geprägten Loci ausgerichtet sind. Aber auch bei der MLMD-Testung ist eine eindeutige Unterscheidung des zugrunde liegenden Mutationstyps als Basis für eine gezielte genetische Beratung erforderlich.

Abstract

All currently known imprinting disorders (ID) have been associated with molecular alterations at disease-specific chromosomal loci. Locus-specific association of some of these disorders has been complicated by the identification of so-called multilocus methylation defects (MLMD). In addition to aberrant methylation at disease-specific loci, MLMD also affects other loci. Clinically, the majority of patients show symptoms of a single ID, but some overlapping phenotypes have been described. Furthermore, cases of patients with the same MLMD pattern but different clinical symptoms have also been reported. Molecular tests aimed at identifying MLMD should therefore be directed at various imprinted loci. To enable comprehensive genetic counseling, clear differentiation of the type of mutation underlying the ID is also a necessary component of MLMD testing.

This is a preview of subscription content, access via your institution.

Abb. 1

Literatur

  1. 1.

    Mackay DJ, Boonen SE, Clayton-Smith J et al (2006) A maternal hypomethylation syndrome presenting as transient neonatal diabetes mellitus. Hum Genet 120:262–269

    PubMed  Article  CAS  Google Scholar 

  2. 2.

    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

    PubMed  Article  CAS  Google Scholar 

  3. 3.

    Azzi S, Rossignol S, Steunou V et al (2009) Multilocus analysis in a large cohort of 11p15-related foetal growth disorders (Russell Silver and Beckwith Wiedemann syndromes) reveals simultaneous loss of methylation at paternal and maternal imprinted loci. Hum Mol Genet 18:4724–4733

    PubMed  Article  CAS  Google Scholar 

  4. 4.

    Begemann M, Spengler S, Kanber D et al (2011) Silver-Russell patients showing a broad range of ICR1 and ICR2 hypomethylation in different tissues. Clin Genet 80:83–88

    PubMed  Article  CAS  Google Scholar 

  5. 5.

    Varrault A, Gueydan C, Delalbre A et al (2006) Zac1 regulates an imprinted gene network critically involved in the control of embryonic growth. Developmental Cell 11:711–722

    PubMed  Article  CAS  Google Scholar 

  6. 6.

    Arima T, Kamikihara T, Hayashida T et al (2005) ZAC, LIT1 (KCNQ1OT1) and p57KIP2 (CDKN1C) are in an imprinted gene network that may play a role in Beckwith-Wiedemann syndrome. Nucleic Acids Res 11:33:2650–2660

    Google Scholar 

  7. 7.

    Sandhu KS, Shi C, Sjölinder M et al (2009) Nonallelic transvection of multiple imprinted loci is organised by the H19 imprinting control region during germline development. Genes Develop 23:2598–2603

    PubMed  Article  CAS  Google Scholar 

  8. 8.

    Roach JC, Glusman G, Smit AF et al (2010) Analysis of genetic inheritance in a family quartet by whole-genome sequencing. Science 328:636–639

    PubMed  Article  CAS  Google Scholar 

  9. 9.

    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

    PubMed  Article  CAS  Google Scholar 

  10. 10.

    Sparago A, Cerrato F, Vernucci M et al (2004) Microdeletions in the human H19 DMR result in loss of IGF2 imprinting and Beckwith-Wiedemann syndrome. Nat Genet 36:958–960

    PubMed  Article  CAS  Google Scholar 

  11. 11.

    Prawitt D, Enklaar T, Gärtner-Rupprecht B et al (2005) Microdeletion of target sites for insulator protein CTCF in a chromosome 11p15 imprinting center in Beckwith-Wiedemann syndrome and Wilms‘ tumor. Proc Natl Acad Sci USA 102:4085–4090

    PubMed  Article  CAS  Google Scholar 

  12. 12.

    Cerrato F, Sparago A, Verde G et al (2008) Different mechanisms cause imprinting defects at the IGF2/H19 locus in Beckwith-Wiedemann syndrome and Wilms‘ tumour. Hum Mol Genet 15:1427–1435

    Article  Google Scholar 

  13. 13.

    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

    PubMed  Article  CAS  Google Scholar 

  14. 14.

    Kelsey G (2010) Imprinting on chromosome 20: tissue-specific imprinting and imprinting mutations in the GNAS locus. Am J Med Genet 154C:377–386

    PubMed  Article  CAS  Google Scholar 

  15. 15.

    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

    PubMed  Article  CAS  Google Scholar 

  16. 16.

    Zhang P, Dixon M, Zucchelli M et al (2008) Expression analysis of the NLRP gene family suggests a role in human preimplantation development. PLoS One 23:e2755

    Article  Google Scholar 

  17. 17.

    Murdoch S, Djuric U, Mazhar B et al (2006) Mutations in NALP7 cause recurrent hydatidiform moles and reproductive wastage in humans. Nat Genet 38:300–302

    PubMed  Article  CAS  Google Scholar 

  18. 18.

    Djuric U, El-Maarri O, Lamb B et al (2006) Familial molar tissues due to mutations in the inflammatory gene, NALP7, have normal postzygotic DNA methylation. Hum Genet 120:390–395

    PubMed  Article  CAS  Google Scholar 

  19. 19.

    Kou YC, Shao L, Peng HH, Rosetta R et al (2008) A recurrent intragenic genomic duplication, other novel mutations in NLRP7 and imprinting defects in recurrent biparental hydatidiform moles. Mol Hum Reprod 14:33–40

    PubMed  Article  CAS  Google Scholar 

  20. 20.

    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

    PubMed  Article  Google Scholar 

  21. 21.

    Begemann M, Spengler S, Kordaß U et al (2012) Segmental maternal uniparental disomy 7q associated with DLK1/GTL2 (14q32) hypomethylation. Am J Med Genet A 158A:423–428

    PubMed  Article  Google Scholar 

  22. 22.

    Howell CY, Bestor TH, Ding F et al (2004) Genomic imprinting disrupted by a maternal effect mutation in the Dnmt1 gene. Cell 104:829–838

    Article  Google Scholar 

  23. 23.

    Cirio MC, Martel J, Mann M et al (2008) DNA methyltransferase 1o functions during preimplantation development to preclude a profound level of epigenetic variation. Dev Biol 324:139–150

    PubMed  Article  CAS  Google Scholar 

  24. 24.

    Xu GL, Bestor TH, Bourc’his D et al (1999) Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene. Nature 402:187–191

    PubMed  Article  CAS  Google Scholar 

  25. 25.

    Bliek J, Alders M, Maas SM et al (2009) Lessons from BWS twins: complex maternal and paternal hypomethylation and a common source of haematopoietic stem cells. Eur J Hum Genet 17:1625–1634

    PubMed  Article  CAS  Google Scholar 

  26. 26.

    Ramsden SC, Clayton-Smith J, Birch R et al (2010) Practice guidelines for the molecular analysis of Prader-Willi and Angelman syndromes. BMC Med Genet 11:70

    PubMed  Article  Google Scholar 

  27. 27.

    Eggermann T, Begemann M, Binder G et al (2010) Silver-Russell syndrome: genetic basis and molecular genetic testing. Orphanet J Rare Dis 5:19

    PubMed  Article  Google Scholar 

  28. 28.

    Netchine I, Rossignol S, Dufourg MN et al (2007) 11p15 imprinting center region 1 loss of methylation is a common and specific cause of typical Russell-Silver syndrome: clinical scoring system and epigenetic-phenotypic correlations. J Clin Endocrinol Metab 92:3148–3154

    PubMed  Article  CAS  Google Scholar 

  29. 29.

    Bartholdi D, Krajewska-Walasek M, Ounap K et al (2009) Epigenetic mutations of the imprinted IGF2-H19 domain in Silver-Russell syndrome (SRS): results from a large cohort of patients with SRS and SRS-like phenotypes. J Med Genet 46:192–197

    PubMed  Article  CAS  Google Scholar 

  30. 30.

    Gogiel M, Begemann M, Spengler S et al (2012) Genome-wide paternal uniparental disomy mosaicism in a woman with Beckwith-Wiedemann syndrome and ovarian steroid cell tumour. Eur J Hum Genet (in press)

  31. 31.

    Behnecke A, Hinderhofer K, Jauch A et al (2012) Silver-Russell syndrome due to maternal uniparental disomy 7 and a familial reciprocal translocation t(7;13). Clin Genet 82:494–498

    PubMed  Article  CAS  Google Scholar 

  32. 32.

    Perez-Nanclares G, Romanelli V et al (2012) Detection of hypomethylation syndrome among patients with epigenetic alterations at the GNAS locus. J Clin Endocrinol Metab 97:E1060–E1067

    PubMed  Article  CAS  Google Scholar 

  33. 33.

    Rossignol S, Steunou V, Chalas C et al (2006) The epigenetic imprinting defect of patients with Beckwith-Wiedemann syndrome born after assisted reproductive technology is not restricted to the 11p15 region. J Med Genet 43:902–907

    PubMed  Article  CAS  Google Scholar 

  34. 34.

    Bliek J, Verde G, Callaway J et al (2009) Hypomethylation at multiple maternally methylated imprinted regions including PLAGL1 and GNAS loci in Beckwith-Wiedemann syndrome. Eur J Hum Genet 17:611–619

    PubMed  Article  CAS  Google Scholar 

  35. 35.

    Lim D, Bowdin SC, Tee L et al (2009) Clinical and molecular genetic features of Beckwith-Wiedemann syndrome associated with assisted reproductive technologies. Hum Reprod 24:741–747

    PubMed  Article  Google Scholar 

  36. 36.

    Turner CL, Mackay DM, Callaway JL et al (2010) Methylation analysis of 79 patients with growth restriction reveals novel patterns of methylation change at imprinted loci. Eur J Med Genet 17:648–655

    Google Scholar 

  37. 37.

    Baple EL, Poole RL, Mansour S et al (2011) An a typical case of hypomethylation at multiple imprinted loci. Eur J Hum Genet 19:360–362

    PubMed  Article  Google Scholar 

  38. 38.

    Adler D (1994) Idiogram Album: Human. Copyright © 1994 David Adler

Download references

Danksagung

Die Autoren sind Mitglieder des vom Bundesministerium für Bildung und Forschung geförderten nationalen Netzwerks „Imprinting Diseases“ (Förderkennzeichen: 01GM0884).

Interessenkonflikt

Der korrespondierende Autor gibt für sich und seine Koautoren an, dass kein Interessenkonflikt besteht.

Author information

Affiliations

Authors

Corresponding author

Correspondence to T. Eggermann.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Eggermann, T., Begemann, M., Soellner, L. et al. Molekulargenetische Diagnostik von Imprintingerkrankungen. medgen 25, 5–14 (2013). https://doi.org/10.1007/s11825-012-0368-2

Download citation

Schlüsselwörter

  • Genomisches Imprinting
  • DNA-Methylierung
  • Multilocussequenztypisierung
  • Angelman-Syndrom
  • Prader-Willi-Syndrom

Keywords

  • Genomic imprinting
  • DNA methylation
  • Multilocus sequence typing
  • Angelman syndrome
  • Prader-Willi syndrome