Journal of Genetic Medicine

  • 제18권1호
  • /
  • Pages.24-30
  • /
  • 2021
  • /
  • 1226-1769(pISSN)
  • /
  • 2383-8442(eISSN)
대한의학유전학회 (Korean Society of Medical Genetics and Genomics)
권호 표지
DOI QR코드

DOI QR Code

Molecular characterization in chromosome 11p15.5 related imprinting disorders Beckwith-Wiedemann and Silver-Russell syndromes

  • Shin, Young-Lim (Department of Pediatrics, Soonchunhyang University Bucheon Hospital, Soonchunhyang University College of Medicine)
  • 투고 : 2021.05.24
  • 심사 : 2021.06.17
  • 발행 : 2021.06.30
PDF 다운로드
⟨ 이전 논문 다음 논문 ⟩

초록

Epigenetics deals with modifications in gene expression, without altering the underlying DNA sequence. Genomic imprinting is a complex epigenetic phenomenon that refers to parent-of-origin-specific gene expression. Beckwith-Wiedemann syndrome (BWS) and Silver-Russell syndrome (SRS) are congenital imprinting disorders with mirror opposite alterations at the genomic loci in 11p15.5 and opposite phenotypes. BWS and SRS are important imprinting disorders with the increase of knowledge of genetic and epigenetic mechanisms. Altered expression of the imprinted genes in 11p15.5, especially IGF2 and CDKN1C, affects fetal and postnatal growth. A wide range of imprinting defects at multiple loci, instead of a restricted locus, has been shown in some patients with either BWS or SRS. The development of new high-throughput assays will make it possible to allow accurate diagnosis, personalized therapy, and informative genetic counseling.

키워드

참고문헌

  1. Demars J, Gicquel C. Epigenetic and genetic disturbance of the imprinted 11p15 region in Beckwith-Wiedemann and Silver-Russell syndromes. Clin Genet 2012;81:350-61. https://doi.org/10.1111/j.1399-0004.2011.01822.x
  2. Elhamamsy AR. Role of DNA methylation in imprinting disorders: an updated review. J Assist Reprod Genet 2017;34:549-62. https://doi.org/10.1007/s10815-017-0895-5
  3. Moore LD, Le T, Fan G. DNA methylation and its basic function. Neuropsychopharmacology 2013;38:23-38. https://doi.org/10.1038/npp.2012.112
  4. Maupetit-Mehouas S, Montibus B, Nury D, Tayama C, Wassef M, Kota SK, et al. Imprinting control regions (ICRs) are marked by mono-allelic bivalent chromatin when transcriptionally inactive. Nucleic Acids Res 2016;44:621-35. https://doi.org/10.1093/nar/gkv960
  5. Babak T, DeVeale B, Tsang EK, Zhou Y, Li X, Smith KS, et al. Genetic conflict reflected in tissue-specific maps of genomic imprinting in human and mouse. Nat Genet 2015;47:544-9. https://doi.org/10.1038/ng.3274
  6. Hanna CW, Kelsey G. The specification of imprints in mammals. Heredity (Edinb) 2014;113:176-83. https://doi.org/10.1038/hdy.2014.54
  7. Azzi S, Abi Habib W, Netchine I. Beckwith-Wiedemann and Russell-Silver syndromes: from new molecular insights to the comprehension of imprinting regulation. Curr Opin Endocrinol Diabetes Obes 2014;21:30-8. https://doi.org/10.1097/MED.0000000000000037
  8. Soellner L, Begemann M, Mackay DJ, Gronskov K, Tumer Z, Maher ER, et al. Recent advances in imprinting disorders. Clin Genet 2017;91:3-13. https://doi.org/10.1111/cge.12827
  9. Abramowitz LK, Bartolomei MS. Genomic imprinting: recognition and marking of imprinted loci. Curr Opin Genet Dev 2012;22:72-8. https://doi.org/10.1016/j.gde.2011.12.001
  10. Ulaner GA, Yang Y, Hu JF, Li T, Vu TH, Hoffman AR. CTCF binding at the insulin-like growth factor-II (IGF2)/H19 imprinting control region is insufficient to regulate IGF2/H19 expression in human tissues. Endocrinology 2003;144:4420-6. https://doi.org/10.1210/en.2003-0681
  11. Beygo J, Citro V, Sparago A, De Crescenzo A, Cerrato F, Heitmann M, et al. The molecular function and clinical phenotype of partial deletions of the IGF2/H19 imprinting control region depends on the spatial arrangement of the remaining CTCF-binding sites. Hum Mol Genet 2013;22:544-57. https://doi.org/10.1093/hmg/dds465
  12. Higashimoto K, Soejima H, Saito T, Okumura K, Mukai T. Imprinting disruption of the CDKN1C/KCNQ1OT1 domain: the molecular mechanisms causing Beckwith-Wiedemann syndrome and cancer. Cytogenet Genome Res 2006;113:306-12. https://doi.org/10.1159/000090846
  13. Vora N, Bianchi DW. Genetic considerations in the prenatal diagnosis of overgrowth syndromes. Prenat Diagn 2009;29:923-9. https://doi.org/10.1002/pd.2319
  14. Mussa A, Russo S, De Crescenzo A, Chiesa N, Molinatto C, Selicorni A, et al. Prevalence of Beckwith-Wiedemann syndrome in North West of Italy. Am J Med Genet A 2013;161A:2481-6.
  15. Cooper WN, Luharia A, Evans GA, Raza H, Haire AC, Grundy R, et al. Molecular subtypes and phenotypic expression of Beckwith-Wiedemann syndrome. Eur J Hum Genet 2005;13:1025-32. https://doi.org/10.1038/sj.ejhg.5201463
  16. Weksberg R, Shuman C, Beckwith JB. Beckwith-Wiedemann syndrome. Eur J Hum Genet 2010;18:8-14. https://doi.org/10.1038/ejhg.2009.106
  17. Gaston V, Le Bouc Y, Soupre V, Burglen L, Donadieu J, Oro H, et al. Analysis of the methylation status of the KCNQ1OT and H19 genes in leukocyte DNA for the diagnosis and prognosis of Beckwith-Wiedemann syndrome. Eur J Hum Genet 2001;9:409-18. https://doi.org/10.1038/sj/ejhg/5200649
  18. Eggermann T, Perez de Nanclares G, Maher ER, Temple IK, Tumer Z, Monk D, et al. Imprinting disorders: a group of congenital disorders with overlapping patterns of molecular changes affecting imprinted loci. Clin Epigenetics 2015;7:123. https://doi.org/10.1186/s13148-015-0143-8
  19. Brioude F, Kalish JM, Mussa A, Foster AC, Bliek J, Ferrero GB, et al. Expert consensus document: clinical and molecular diagnosis, screening and management of Beckwith-Wiedemann syndrome: an international consensus statement. Nat Rev Endocrinol 2018;14:229-49. https://doi.org/10.1038/nrendo.2017.166
  20. Weksberg R, Nishikawa J, Caluseriu O, Fei YL, Shuman C, Wei C, et al. Tumor development in the Beckwith-Wiedemann syndrome is associated with a variety of constitutional molecular 11p15 alterations including imprinting defects of KCNQ1OT1. Hum Mol Genet 2001;10:2989-3000. https://doi.org/10.1093/hmg/10.26.2989
  21. Begemann M, Spengler S, Gogiel M, Grasshoff U, Bonin M, Betz RC, et al. Clinical significance of copy number variations in the 11p15.5 imprinting control regions: new cases and review of the literature. J Med Genet 2012;49:547-53. https://doi.org/10.1136/jmedgenet-2012-100967
  22. Cooper WN, Curley R, Macdonald F, Maher ER. Mitotic recombination and uniparental disomy in Beckwith-Wiedemann syndrome. Genomics 2007;89:613-7. https://doi.org/10.1016/j.ygeno.2007.01.005
  23. Sasaki K, Soejima H, Higashimoto K, Yatsuki H, Ohashi H, Yakabe S, et al. Japanese and North American/European patients with BeckwithWiedemann syndrome have different frequencies of some epigenetic and genetic alterations. Eur J Hum Genet 2007;15:1205-10. https://doi.org/10.1038/sj.ejhg.5201912
  24. Demars J, Shmela ME, Rossignol S, Okabe J, Netchine I, Azzi S, et al. 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 2010;19:803-14. https://doi.org/10.1093/hmg/ddp549
  25. Abi Habib W, Azzi S, Brioude F, Steunou V, Thibaud N, Das Neves C, et al. Extensive investigation of the IGF2/H19 imprinting control region reveals novel OCT4/SOX2 binding site defects associated with specific methylation patterns in Beckwith-Wiedemann syndrome. Hum Mol Genet 2014;23:5763-73. https://doi.org/10.1093/hmg/ddu290
  26. Romanelli V, Meneses HN, Fernandez L, Martinez-Glez V, Gracia-Bouthelier R, F Fraga M, et al. Beckwith-Wiedemann syndrome and uniparental disomy 11p: fine mapping of the recombination breakpoints and evaluation of several techniques. Eur J Hum Genet 2011;19:416-21. https://doi.org/10.1038/ejhg.2010.236
  27. Eggermann T, Binder G, Brioude F, Maher ER, Lapunzina P, Cubellis MV, et al. CDKN1C mutations: two sides of the same coin. Trends Mol Med 2014;20:614-22. https://doi.org/10.1016/j.molmed.2014.09.001
  28. Brioude F, Netchine I, Praz F, Le Jule M, Calmel C, Lacombe D, et al. Mutations of the imprinted CDKN1C gene as a cause of the overgrowth Beckwith-Wiedemann syndrome: clinical spectrum and functional characterization. Hum Mutat 2015;36:894-902. https://doi.org/10.1002/humu.22824
  29. Niemitz EL, DeBaun MR, Fallon J, Murakami K, Kugoh H, Oshimura M, et al. Microdeletion of LIT1 in familial Beckwith-Wiedemann syndrome. Am J Hum Genet 2004;75:844-9. https://doi.org/10.1086/425343
  30. Sparago A, Cerrato F, Vernucci M, Ferrero GB, Silengo MC, Riccio A. Microdeletions in the human H19 DMR result in loss of IGF2 imprinting and Beckwith-Wiedemann syndrome. Nat Genet 2004;36:958-60. https://doi.org/10.1038/ng1410
  31. Netchine I, Rossignol S, Dufourg MN, Azzi S, Rousseau A, Perin L, et al. 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 2007;92:3148-54. https://doi.org/10.1210/jc.2007-0354
  32. Gicquel C, Rossignol S, Cabrol S, Houang M, Steunou V, Barbu V, et al. Epimutation of the telomeric imprinting center region on chromosome 11p15 in Silver-Russell syndrome. Nat Genet 2005;37:1003-7. https://doi.org/10.1038/ng1629
  33. Binder G, Seidel AK, Martin DD, Schweizer R, Schwarze CP, Wollmann HA, et al. The endocrine phenotype in Silver-Russell syndrome is defined by the underlying epigenetic alteration. J Clin Endocrinol Metab 2008;93:1402-7. https://doi.org/10.1210/jc.2007-1897
  34. Kotzot D, Schmitt S, Bernasconi F, Robinson WP, Lurie IW, Ilyina H, et al. Uniparental disomy 7 in Silver-Russell syndrome and primordial growth retardation. Hum Mol Genet 1995;4:583-7. https://doi.org/10.1093/hmg/4.4.583
  35. Eggermann T, Heilsberg AK, Bens S, Siebert R, Beygo J, Buiting K, et al. Additional molecular findings in 11p15-associated imprinting disorders: an urgent need for multi-locus testing. J Mol Med (Berl) 2014;92:769-77. https://doi.org/10.1007/s00109-014-1141-6
  36. Bruce S, Hannula-Jouppi K, Puoskari M, Fransson I, Simola KO, Lipsanen-Nyman M, et al. Submicroscopic genomic alterations in Silver-Russell syndrome and Silver-Russell-like patients. J Med Genet 2010;47:816-22. https://doi.org/10.1136/jmg.2009.069427
  37. Spengler S, Begemann M, Ortiz Bruchle N, Baudis M, Denecke B, Kroisel PM, et al. Molecular karyotyping as a relevant diagnostic tool in children with growth retardation with Silver-Russell features. J Pediatr 2012;161:933-42. https://doi.org/10.1016/j.jpeds.2012.04.045
  38. Fuke T, Mizuno S, Nagai T, Hasegawa T, Horikawa R, Miyoshi Y, et al. Molecular and clinical studies in 138 Japanese patients with Silver-Russell syndrome. PLoS One 2013;8:e60105. https://doi.org/10.1371/journal.pone.0060105
  39. Fokstuen S, Kotzot D. Chromosomal rearrangements in patients with clinical features of Silver-Russell syndrome. Am J Med Genet A 2014;164A:1595-605. https://doi.org/10.1002/ajmg.a.36464
  40. Azzi S, Salem J, Thibaud N, Chantot-Bastaraud S, Lieber E, Netchine I, et al. A prospective study validating a clinical scoring system and demonstrating phenotypical-genotypical correlations in Silver-Russell syndrome. J Med Genet 2015;52:446-53. https://doi.org/10.1136/jmedgenet-2014-102979
  41. Cytrynbaum C, Chong K, Hannig V, Choufani S, Shuman C, Steele L, et al. Genomic imbalance in the centromeric 11p15 imprinting center in three families: further evidence of a role for IC2 as a cause of Russell-Silver syndrome. Am J Med Genet A 2016;170:2731-9. https://doi.org/10.1002/ajmg.a.37819
  42. Gronskov K, Poole RL, Hahnemann JM, Thomson J, Tumer Z, Brondum-Nielsen K, et al. Deletions and rearrangements of the H19/IGF2 enhancer region in patients with Silver-Russell syndrome and growth retardation. J Med Genet 2011;48:308-11. https://doi.org/10.1136/jmg.2010.086504
  43. Begemann M, Zirn B, Santen G, Wirthgen E, Soellner L, Buttel HM, et al. Paternally inherited IGF2 mutation and growth restriction. N Engl J Med 2015;373:349-56. https://doi.org/10.1056/NEJMoa1415227
  44. Bullman H, Lever M, Robinson DO, Mackay DJ, Holder SE, Wakeling EL. Mosaic maternal uniparental disomy of chromosome 11 in a patient with Silver-Russell syndrome. J Med Genet 2008;45:396-9. https://doi.org/10.1136/jmg.2007.057059
  45. Brioude F, Oliver-Petit I, Blaise A, Praz F, Rossignol S, Le Jule M, et al. CDKN1C mutation affecting the PCNA-binding domain as a cause of familial Russell Silver syndrome. J Med Genet 2013;50:823-30. https://doi.org/10.1136/jmedgenet-2013-101691
  46. De Crescenzo A, Citro V, Freschi A, Sparago A, Palumbo O, Cubellis MV, et al. A splicing mutation of the HMGA2 gene is associated with Silver-Russell syndrome phenotype. J Hum Genet 2015;60:287-93. https://doi.org/10.1038/jhg.2015.29
  47. Abi Habib W, Brioude F, Edouard T, Bennett JT, Lienhardt-Roussie A, Tixier F, et al. Genetic disruption of the oncogenic HMGA2-PLAG1-IGF2 pathway causes fetal growth restriction. Genet Med 2018;20:250-8. https://doi.org/10.1038/gim.2017.105
  48. Hubner CT, Meyer R, Kenawy A, Ambrozaityte L, Matuleviciene A, Kraft F, et al. HMGA2 variants in Silver-Russell syndrome: homozygous and heterozygous occurrence. J Clin Endocrinol Metab 2020;105:dgaa273.
  49. Wesseler K, Kraft F, Eggermann T. Molecular and clinical opposite findings in 11p15.5 associated imprinting disorders: characterization of basic mechanisms to improve clinical management. Int J Mol Sci 2019;20:4219. https://doi.org/10.3390/ijms20174219
  50. Valente FM, Sparago A, Freschi A, Hill-Harfe K, Maas SM, Frints SGM, et al. Transcription alterations of KCNQ1 associated with imprinted methylation defects in the Beckwith-Wiedemann locus. Genet Med 2019;21:1808-20. https://doi.org/10.1038/s41436-018-0416-7
  51. Wakeling EL, Brioude F, Lokulo-Sodipe O, O'Connell SM, Salem J, Bliek J, et al. Diagnosis and management of Silver-Russell syndrome: first international consensus statement. Nat Rev Endocrinol 2017;13:105-24. https://doi.org/10.1038/nrendo.2016.138
  52. Mussa A, Molinatto C, Baldassarre G, Riberi E, Russo S, Larizza L, et al. Cancer risk in Beckwith-Wiedemann syndrome: a systematic review and meta-analysis outlining a novel (epi)genotype specific histotype targeted screening protocol. J Pediatr 2016;176:142-9.e1. https://doi.org/10.1016/j.jpeds.2016.05.038
  53. Azzi S, Rossignol S, Le Bouc Y, Netchine I. Lessons from imprinted multilocus loss of methylation in human syndromes: a step toward understanding the mechanisms underlying these complex diseases. Epigenetics 2010;5:373-7. https://doi.org/10.4161/epi.5.5.11851
  54. Court F, Martin-Trujillo A, Romanelli V, Garin I, Iglesias-Platas I, Salafsky I, et al. Genome-wide allelic methylation analysis reveals disease-specific susceptibility to multiple methylation defects in imprinting syndromes. Hum Mutat 2013;34:595-602. https://doi.org/10.1002/humu.22276
  55. Maeda T, Higashimoto K, Jozaki K, Yatsuki H, Nakabayashi K, Makita Y, et al. Comprehensive and quantitative multilocus methylation analysis reveals the susceptibility of specific imprinted differentially methylated regions to aberrant methylation in Beckwith-Wiedemann syndrome with epimutations. Genet Med 2014;16:903-12. https://doi.org/10.1038/gim.2014.46
  56. Boonen SE, Porksen S, Mackay DJ, Oestergaard E, Olsen B, Brondum-Nielsen K, et al. Clinical characterisation of the multiple maternal hypomethylation syndrome in siblings. Eur J Hum Genet 2008;16:453-61. https://doi.org/10.1038/sj.ejhg.5201993
  57. Sano S, Matsubara K, Nagasaki K, Kikuchi T, Nakabayashi K, Hata K, et al. Beckwith-Wiedemann syndrome and pseudohypoparathyroidism type Ib in a patient with multilocus imprinting disturbance: a female-dominant phenomenon? J Hum Genet 2016;61:765-9. https://doi.org/10.1038/jhg.2016.45
  58. Bliek J, Verde G, Callaway J, Maas SM, De Crescenzo A, Sparago A, et al. Hypomethylation at multiple maternally methylated imprinted regions including PLAGL1 and GNAS loci in Beckwith-Wiedemann syndrome. Eur J Hum Genet 2009;17:611-9. https://doi.org/10.1038/ejhg.2008.233
  59. Poole RL, Docherty LE, Al Sayegh A, Caliebe A, Turner C, Baple E, et al. Targeted methylation testing of a patient cohort broadens the epigenetic and clinical description of imprinting disorders. Am J Med Genet A 2013;161A:2174-82.