DNA replication is altered in Immunodeficiency Centromeric instability Facial anomalies (ICF) cells carrying DNMT3B mutations

Lana, Erica; Mégarbané, André; Tourrière, Hélène; Sarda, Pierre; Lefranc, Gérard; Claustres, Mireille; Sario, Albertina De

doi:10.1038/ejhg.2012.41

Cited by 22 publications

(15 citation statements)

References 31 publications

(51 reference statements)

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“…Additional molecular mechanisms acting in trans , such as perturbed nuclear organization as a result of the altered juxtacentromeric or telomeric heterochromatin organization [18-20], deregulated expression of small regulatory microRNAs (miRNA) [21] or changes in replication timing [22] may also have a deep impact on the deregulation of gene expression programs in ICF patients. However, these perturbed profiles showed great variability, probably reflecting phenotypic variability between patients and cell culture effects, and no common or distinguishing molecular signatures could be reliably established from these studies.…”

Section: Introductionmentioning

confidence: 99%

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

Velasco

Walton

Sterlin

et al. 2014

Orphanet J Rare Dis

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BackgroundImmunodeficiency 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.MethodWe 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.ResultsWe 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.ConclusionsEarly 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.

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Section: Introductionmentioning

confidence: 99%

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

Velasco

Walton

Sterlin

et al. 2014

Orphanet J Rare Dis

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“…This lets us speculate that it is adaptation to the changing environment leading to changes of epigenetic status, which in turn induce the increased nucleotide diversity. A recent study reported that replication defects, which result from chromatin changes caused by a DNMT3B mutation, can cause differences in individuals with mutations (Lana et al 2012), indicating a correlation between methylation status and mutation rates. CpG content dependent correlation between non-CpG and CpG mutations (with a threshold of ~0.53% CpG content) (Walser et al 2008; Walser and Furano 2010) also supports a role for methylation in DNA mutation.…”

Section: Resultsmentioning

confidence: 99%

Accelerated DNA evolution in rats is driven by differential methylation in sperm

Liu

Lian

Ling

et al. 2015

Preprint

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Lamarckian inheritance has been largely discredited until the recent discovery of transgenerational epigenetic inheritance. However, transgenerational epigenetic inheritance is still under debate for unable to rule out DNA sequence changes as the underlying cause for heritability. Here, through profiling of the sperm methylomes and genomes of two recently diverged rat subspecies, we analyzed the relationship between epigenetic variation and DNA variation, and their relative contribution to evolution of species. We found that only epigenetic markers located in differentially methylated regions (DMRs) between subspecies, but not within subspecies, can be stably and effectively passed through generations. DMRs in response to both random and stable environmental difference show increased nucleotide diversity, and we demonstrated that it is variance of methylation level but not deamination caused by methylation driving increasing of nucleotide diversity in DMRs, indicating strong relationship between environment-associated changes of chromatin accessibility and increased nucleotide diversity. Further, we detected that accelerated fixation of DNA variants occur only in inter-subspecies DMRs in response to stable environmental difference but not intra-subspecies DMRs in response to random environmental difference or non-DMRs, indicating that this process is possibly driven by environment-associated fixation of divergent methylation status. Our results thus establish a bridge between Lamarckian inheritance and Darwinian selection.

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“…ICF-patient fibroblasts carrying abnormally short telomeres at a low population doubling enter senescence prematurely. 47 Other observations likely related to the changes in the ICF epigenome include altered DNA replication with heterochromatic genes replicating earlier in the S-phase, 48 activation of juxtacentromeric heterochromatic genes, 49 and changes in intranuclear organization of chromosomes or chromosome domains. 50À52 DIAGNOSTICS Without cytogenetic confirmation, most patients with ICF syndrome will be classified as suffering from common variable immunodeficiency (CVID) according to the WHO classification for primary immunodeficiencies.…”

Section: Chromosomal Abnormalities Hypomethylation and Nuclear Orgamentioning

confidence: 97%

Centromeric Instability in ICF Syndrome

Weemaes

Maarel

2014

Stiehm's Immune Deficiencies

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DNA replication is altered in Immunodeficiency Centromeric instability Facial anomalies (ICF) cells carrying DNMT3B mutations

Cited by 22 publications

References 31 publications

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

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

Accelerated DNA evolution in rats is driven by differential methylation in sperm

Centromeric Instability in ICF Syndrome

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