Germline genes hypomethylation and expression define a molecular signature in peripheral blood of ICF patients: implications for diagnosis and etiology

Orphanet Journal of Rare Diseases

Claire Francastel³  Capucine Picard⁵  Hiroyuki Sasaki²  André Mégarbané⁴  Fanny Fouyssac⁶  Yuya Ito²  Hirohisa Nitta²  Sabrine Hédouin³  Delphine Sterlin¹  Emma L Walton³  Guillaume Velasco³ 

[1]Center for the Study of Primary Immunodeficiencies, Assistance Publique-Hôpitaux de Paris, Necker Hospital, Paris, France

[2]Division of Epigenomics and Development, Department of Molecular Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan

[3]Université Paris Diderot-Paris7, CNRS UMR7216, Epigénétique et Destin Cellulaire, Case Courrier 7042

[4] 35, rue Hélène Brion, 75205 Paris, France

[5]Unité de Génétique Médicale et laboratoire associé, INSERM UMR S_910, Faculté de Médecine, Université Saint Joseph, Beirut, Lebanon

[6]Imagine Institute, University Paris Descartes, Sorbonne Paris Cité, Paris, France

[7]Service d'Hémato-oncologie Pédiatrique et Transplantations Médullaires, Centre Hospitalier Universitaire de Nancy, Hôpital Brabois Enfants, Vandœuvre-lès-Nancy, France

关键词: X-linked;    Genes;    Biological markers/etiology;    Biological markers/diagnosis use;    Gene expression;    Satellite;    DNA;    Heterochromatin;    DNA methylation;    Agammaglobulinemia;   

Others  :  863181
DOI  :  10.1186/1750-1172-9-56

 received in 2014-02-07, accepted in 2014-04-11,  发布年份 2014

【 摘 要 】

Background

Immunodeficiency Centromeric Instability and Facial anomalies (ICF) is a rare autosomal recessive disease characterized by reduction in serum immunoglobulins with severe recurrent infections, facial dysmorphism, and more variable symptoms including mental retardation. ICF is directly related to a genomic methylation defect that mainly affects juxtacentromeric heterochromatin regions of certain chromosomes, leading to chromosomal rearrangements that constitute a hallmark of this syndrome upon cytogenetic testing. Mutations in the de novo DNA methyltransferase DNMT3B, the protein ZBTB24 of unknown function, or loci that remain to be identified, lie at its origin. Despite unifying features, common or distinguishing molecular signatures are still missing for this disease.

Method

We used the molecular signature that we identified in a mouse model for ICF1 to establish transcriptional biomarkers to facilitate diagnosis and understanding of etiology of the disease. We assayed the expression and methylation status of a set of genes whose expression is normally restricted to germ cells, directly in whole blood samples and epithelial cells of ICF patients.

Results

We report that DNA hypomethylation and expression of MAEL and SYCE1 represent robust biomarkers, easily testable directly from uncultured cells to diagnose the most prevalent sub-type of the syndrome. In addition, we identified the first unifying molecular signatures for ICF patients. Of importance, we validated the use of our biomarkers to diagnose a baby born to a family with a sick child. Finally, our analysis revealed unsuspected complex molecular signatures in two ICF patients suggestive of a novel genetic etiology for the disease.

Conclusions

Early diagnosis of ICF syndrome is crucial since early immunoglobulin supplementation can improve the course of disease. However, ICF is probably underdiagnosed, especially in patients that present with incomplete phenotype or born to families with no affected relatives. The specific and robust biomarkers identified in this study could be introduced into routine clinical immunology or neurology departments to facilitate testing of patients with suspected ICF syndrome. In addition, as exemplified by two patients with a combination of molecular defects never described before, our data support the search for new types of mutations at the origin of ICF syndrome.

【 授权许可】

   
2014 Velasco et al.; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]Maraschio P, Zuffardi O, Dalla Fior T, Tiepolo L: Immunodeficiency, centromeric heterochromatin instability of chromosomes 1, 9, and 16, and facial anomalies: the ICF syndrome. J Med Genet 1988, 25:173-180.
• [2]Hagleitner MM, Lankester A, Maraschio P, Hulten M, Fryns JP, Schuetz C, Gimelli G, Davies EG, Gennery A, Belohradsky BH, de Groot R, Gerritsen EJ, Mattina T, Howard PJ, Fasth A, Reisli I, Furthner D, Slatter MA, Cant AJ, Cazzola G, van Dijken PJ, van Deuren M, de Greef JC, van der Maarel SM, Weemaes CM: Clinical spectrum of immunodeficiency, centromeric instability and facial dysmorphism (ICF syndrome). J Med Genet 2008, 45:93-99.
• [3]Ehrlich M, Jackson K, Weemaes C: Immunodeficiency, centromeric region instability, facial anomalies syndrome (ICF). Orphan J Rare Dis 2006, 1:2. BioMed Central Full Text
• [4]Xu GL, Bestor TH, Bourc'his D, Hsieh CL, Tommerup N, Bugge M, Hulten M, Qu X, Russo JJ, Viegas-Pequignot E: Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene. Nature 1999, 402:187-191.
• [5]Hansen RS, Wijmenga C, Luo P, Stanek AM, Canfield TK, Weemaes CM, Gartler SM: The DNMT3B DNA methyltransferase gene is mutated in the ICF immunodeficiency syndrome. Proc Natl Acad Sci U S A 1999, 96:14412-14417.
• [6]Okano M, Bell DW, Haber DA, Li E: DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 1999, 99:247-257.
• [7]Gowher H, Jeltsch A: Molecular enzymology of the catalytic domains of the Dnmt3a and Dnmt3b DNA methyltransferases. J Biol Chem 2002, 277:20409-20414.
• [8]Moarefi AH, Chedin F: ICF syndrome mutations cause a broad spectrum of biochemical defects in DNMT3B-mediated de novo DNA methylation. J Mol Biol 2011, 409:758-772.
• [9]Ehrlich M: The ICF syndrome, a DNA methyltransferase 3B deficiency and immunodeficiency disease. Clin Immunol 2003, 109:17-28.
• [10]de Greef JC, Wang J, Balog J, den Dunnen JT, Frants RR, Straasheijm KR, Aytekin C, van der Burg M, Duprez L, Ferster A, Gennery AR, Gimelli G, Reisli I, Schuetz C, Schulz A, Smeets DF, Sznajer Y, Wijmenga C, van Eggermond MC, van Ostaijen-Ten Dam MM, Lankester AC, van Tol MJ, van den Elsen PJ, Weemaes CM, van der Maarel SM: Mutations in ZBTB24 are associated with immunodeficiency, centromeric instability, and facial anomalies syndrome type 2. Am J Hum Genet 2011, 88:796-804.
• [11]Weemaes CM, van Tol MJ, Wang J, van Ostaijen-Ten Dam MM, van Eggermond MC, Thijssen PE, Aytekin C, Brunetti-Pierri N, van der Burg M, Graham Davies E, Ferster A, Furthner D, Gimelli G, Gennery A, Kloeckener-Gruissem B, Meyn S, Powell C, Reisli I, Schuetz C, Schulz A, Shugar A, van den Elsen PJ, van der Maarel SM: Heterogeneous clinical presentation in ICF syndrome: correlation with underlying gene defects. Eur J Hum Genet 2013, 21:1219-1225.
• [12]Jiang YL, Rigolet M, Bourc'his D, Nigon F, Bokesoy I, Fryns JP, Hulten M, Jonveaux P, Maraschio P, Megarbane A, Moncla A, Viegas-Péquignot E: DNMT3B mutations and DNA methylation defect define two types of ICF syndrome. Hum Mutat 2005, 25:56-63.
• [13]Tiepolo L, Maraschio P, Gimelli G, Cuoco C, Gargani GF, Romano C: Multibranched chromosomes 1, 9, and 16 in a patient with combined IgA and IgE deficiency. Hum Genet 1979, 51:127-137.
• [14]Tuck-Muller CM, Narayan A, Tsien F, Smeets DF, Sawyer J, Fiala ES, Sohn OS, Ehrlich M: DNA hypomethylation and unusual chromosome instability in cell lines from ICF syndrome patients. Cytogenet Cell Genet 2000, 89:121-128.
• [15]Ehrlich M, Buchanan KL, Tsien F, Jiang G, Sun B, Uicker W, Weemaes CM, Smeets D, Sperling K, Belohradsky BH, Tommerup N, Misek DE, Rouillard JM, Kuick R, Hanash SM: DNA methyltransferase 3B mutations linked to the ICF syndrome cause dysregulation of lymphogenesis genes. Hum Mol Genet 2001, 10:2917-2931.
• [16]Jin B, Tao Q, Peng J, Soo HM, Wu W, Ying J, Fields CR, Delmas AL, Liu X, Qiu J, Robertson KD: DNA methyltransferase 3B (DNMT3B) mutations in ICF syndrome lead to altered epigenetic modifications and aberrant expression of genes regulating development, neurogenesis and immune function. Hum Mol Genet 2008, 17:690-709.
• [17]Heyn H, Vidal E, Sayols S, Sanchez-Mut JV, Moran S, Medina I, Sandoval J, Simo-Riudalbas L, Szczesna K, Huertas D, Gatto S, Matarazzo MR, Dopazo J, Esteller M: Whole-genome bisulfite DNA sequencing of a DNMT3B mutant patient. Epigenetics 2012, 7:542-550.
• [18]Matarazzo MR, Boyle S, D'Esposito M, Bickmore WA: Chromosome territory reorganization in a human disease with altered DNA methylation. Proc Natl Acad Sci U S A 2007, 104:16546-16551.
• [19]Jefferson A, Colella S, Moralli D, Wilson N, Yusuf M, Gimelli G, Ragoussis J, Volpi EV: Altered intra-nuclear organisation of heterochromatin and genes in ICF syndrome. PLoS One 2010, 5:e11364.
• [20]Yehezkel S, Segev Y, Viegas-Pequignot E, Skorecki K, Selig S: Hypomethylation of subtelomeric regions in ICF syndrome is associated with abnormally short telomeres and enhanced transcription from telomeric regions. Hum Mol Genet 2008, 17:2776-2789.
• [21]Gatto S, Della Ragione F, Cimmino A, Strazzullo M, Fabbri M, Mutarelli M, Ferraro L, Weisz A, D'Esposito M, Matarazzo MR: Epigenetic alteration of microRNAs in DNMT3B-mutated patients of ICF syndrome. Epigenetics 2010, 5:427-443.
• [22]Lana E, Megarbane A, Tourriere H, Sarda P, Lefranc G, Claustres M, De Sario A: DNA replication is altered in Immunodeficiency Centromeric instability Facial anomalies (ICF) cells carrying DNMT3B mutations. Eur J Hum Genet 2012, 20:1044-1050.
• [23]Velasco G, Hube F, Rollin J, Neuillet D, Philippe C, Bouzinba-Segard H, Galvani A, Viegas-Pequignot E, Francastel C: Dnmt3b recruitment through E2F6 transcriptional repressor mediates germ-line gene silencing in murine somatic tissues. Proc Natl Acad Sci U S A 2010, 107:9281-9286.
• [24]Walton EL, Francastel C, Velasco G: Maintenance of DNA methylation: Dnmt3b joins the dance. Epigenetics 2011, 6:1373-1377.
• [25]Brun ME, Lana E, Rivals I, Lefranc G, Sarda P, Claustres M, Megarbane A, De Sario A: Heterochromatic genes undergo epigenetic changes and escape silencing in immunodeficiency, centromeric instability, facial anomalies (ICF) syndrome. PLoS One 2011, 6:e19464.
• [26]Rigolet M, Gregoire A, Lefort G, Blanchet P, Courbes C, Rodiere M, Sarda P, Viegas-Pequignot E: Early prenatal diagnosis of ICF syndrome by mutation detection. Prenat Diagn 2007, 27:1075-1078.
• [27]Nitta H, Unoki M, Ichiyanagi K, Kosho T, Shigemura T, Takahashi H, Velasco G, Francastel C, Picard C, Kubota T, Sasaki H: Three novel ZBTB24 mutations identified in Japanese and Cape Verdean type 2 ICF syndrome patients. J Hum Genet 2013, 58:455-460.
• [28]Maatouk DM, Kellam LD, Mann MR, Lei H, Li E, Bartolomei MS, Resnick JL: DNA methylation is a primary mechanism for silencing postmigratory primordial germ cell genes in both germ cell and somatic cell lineages. Development 2006, 133:3411-3418.
• [29]Antequera F, Boyes J, Bird A: High levels of de novo methylation and altered chromatin structure at CpG islands in cell lines. Cell 1990, 62:503-514.
• [30]Vilain A, Bernardino J, Gerbault-Seureau M, Vogt N, Niveleau A, Lefrancois D, Malfoy B, Dutrillaux B: DNA methylation and chromosome instability in lymphoblastoid cell lines. Cytogenet Cell Genet 2000, 90:93-101.
• [31]Miniou P, Jeanpierre M, Blanquet V, Sibella V, Bonneau D, Herbelin C, Fischer A, Niveleau A, Viegas-Pequignot E: Abnormal methylation pattern in constitutive and facultative (X inactive chromosome) heterochromatin of ICF patients. Hum Mol Genet 1994, 3:2093-2102.
• [32]Hansen RS, Stoger R, Wijmenga C, Stanek AM, Canfield TK, Luo P, Matarazzo MR, D'Esposito M, Feil R, Gimelli G, Weemaes CM, Laird CD, Gartler SM: Escape from gene silencing in ICF syndrome: evidence for advanced replication time as a major determinant. Hum Mol Genet 2000, 9:2575-2587.
• [33]Kaya N, Al-Muhsen S, Al-Saud B, Al-Bakheet A, Colak D, Al-Ghonaium A, Al-Dhekri H, Al-Mousa H, Arnaout R, Al-Owain M, Iqbal M: ICF syndrome in Saudi Arabia: immunological, cytogenetic and molecular analysis. J Clin Immunol 2011, 31:245-252.