Browse
Submit Data
Databases
API
Help

Dataset Information

20 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Mutations in CDCA7 and HELLS cause immunodeficiency-centromeric instability-facial anomalies syndrome.

ABSTRACT: The life-threatening Immunodeficiency, Centromeric Instability and Facial Anomalies (ICF) syndrome is a genetically heterogeneous autosomal recessive disorder. Twenty percent of patients cannot be explained by mutations in the known ICF genes DNA methyltransferase 3B or zinc-finger and BTB domain containing 24. Here we report mutations in the cell division cycle associated 7 and the helicase, lymphoid-specific genes in 10 unexplained ICF cases. Our data highlight the genetic heterogeneity of ICF syndrome; however, they provide evidence that all genes act in common or converging pathways leading to the ICF phenotype.

SUBMITTER: Thijssen PE

PROVIDER: S-EPMC4519989 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

CDCA7 and HELLS mutations undermine nonhomologous end joining in centromeric instability syndrome.

Project description:Mutations in CDCA7 and HELLS that respectively encode a CXXC-type zinc finger protein and an SNF2 family chromatin remodeler cause immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome types 3 and 4. Here, we demonstrate that the classical nonhomologous end joining (C-NHEJ) proteins Ku80 and Ku70, as well as HELLS, coimmunoprecipitated with CDCA7. The coimmunoprecipitation of the repair proteins was sensitive to nuclease treatment and an ICF3 mutation in CDCA7 that impairs its chromatin binding. The functional importance of these interactions was strongly suggested by the compromised C-NHEJ activity and significant delay in Ku80 accumulation at DNA damage sites in CDCA7- and HELLS-deficient HEK293 cells. Consistent with the repair defect, these cells displayed increased apoptosis, abnormal chromosome segregation, aneuploidy, centrosome amplification, and significant accumulation of γH2AX signals. Although less prominent, cells with mutations in the other ICF genes DNMT3B and ZBTB24 (responsible for ICF types 1 and 2, respectively) showed similar defects. Importantly, lymphoblastoid cells from ICF patients shared the same changes detected in the mutant HEK293 cells to varying degrees. Although the C-NHEJ defect alone did not cause CG hypomethylation, CDCA7 and HELLS are involved in maintaining CG methylation at centromeric and pericentromeric repeats. The defect in C-NHEJ may account for some common features of ICF cells, including centromeric instability, abnormal chromosome segregation, and apoptosis.

| S-EPMC6307953 | biostudies-literature

Immunodeficiency, centromeric region instability, facial anomalies syndrome (ICF).

Project description:The Immunodeficiency, Centromeric region instability, Facial anomalies syndrome (ICF) is a rare autosomal recessive disease described in about 50 patients worldwide and characterized by immunodeficiency, although B cells are present, and by characteristic rearrangements in the vicinity of the centromeres (the juxtacentromeric heterochromatin) of chromosomes 1 and 16 and sometimes 9. Other variable symptoms of this probably under-diagnosed syndrome include mild facial dysmorphism, growth retardation, failure to thrive, and psychomotor retardation. Serum levels of IgG, IgM, IgE, and/or IgA are low, although the type of immunoglobulin deficiency is variable. Recurrent infections are the presenting symptom, usually in early childhood. ICF always involves limited hypomethylation of DNA and often arises from mutations in one of the DNA methyltransferase genes (DNMT3B). Much of this DNA hypomethylation is in 1qh, 9qh, and 16qh, regions that are the site of whole-arm deletions, chromatid and chromosome breaks, stretching (decondensation), and multiradial chromosome junctions in mitogen-stimulated lymphocytes. By an unknown mechanism, the DNMT3B deficiency that causes ICF interferes with lymphogenesis (at a step after class switching) or lymphocyte activation. With the identification of DNMT3B as the affected gene in a majority of ICF patients, prenatal diagnosis of ICF is possible. However, given the variety of DNMT3B mutations, a first-degree affected relative should first have both alleles of this gene sequenced. Treatment almost always includes regular infusions of immunoglobulins, mostly intravenously. Recently, bone marrow transplantation has been tried.

| S-EPMC1459120 | biostudies-literature

DNA methylation in disease: Immunodeficiency, Centromeric instability, Facial anomalies syndrome.

Project description:DNA methylation is an epigenetic modification essential for normal mammalian development. Initially associated with gene silencing, more diverse roles for DNA methylation in the regulation of gene expression patterns are increasingly being recognized. Some of these insights come from studying the function of genes that are mutated in human diseases characterized by abnormal DNA methylation landscapes. The first disorder to be associated with congenital defects in DNA methylation was Immunodeficiency, Centromeric instability, Facial anomalies syndrome (ICF). The hallmark of this syndrome is hypomethylation of pericentromeric satellite repeats, with mutations in four genes: DNMT3B, ZBTB24, CDCA7 and HELLS, being linked to the disease. Here, we discuss recent progress in understanding the molecular interactions between these genes and consider current evidence for how aberrant DNA methylation may contribute to the abnormal phenotype present in ICF syndrome patients.

| S-EPMC6923317 | biostudies-literature

Mutations in ZBTB24 are associated with immunodeficiency, centromeric instability, and facial anomalies syndrome type 2.

Project description:Autosomal-recessive immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is mainly characterized by recurrent, often fatal, respiratory and gastrointestinal infections. About 50% of patients carry mutations in the DNA methyltransferase 3B gene (DNMT3B) (ICF1). The remaining patients carry unknown genetic defects (ICF2) but share with ICF1 patients the same immunological and epigenetic features, including hypomethylation of juxtacentromeric repeat sequences. We performed homozygosity mapping in five unrelated ICF2 patients with consanguineous parents and then performed whole-exome sequencing in one of these patients and Sanger sequencing in all to identify mutations in the zinc-finger- and BTB (bric-a-bric, tramtrack, broad complex)-domain-containing 24 (ZBTB24) gene in four consanguineously descended ICF2 patients. Additionally, we found ZBTB24 mutations in an affected sibling pair and in one patient for whom it was not known whether his parents were consanguineous. ZBTB24 belongs to a large family of transcriptional repressors that include members, such as BCL6 and PATZ1, with prominent regulatory roles in hematopoietic development and malignancy. These data thus indicate that ZBTB24 is involved in DNA methylation of juxtacentromeric DNA and in B cell development and/or B and T cell interactions. Because ZBTB24 is a putative DNA-binding protein highly expressed in the lymphoid lineage, we predict that by studying the molecular function of ZBTB24, we will improve our understanding of the molecular pathophysiology of ICF syndrome and of lymphocyte biology in general.

| S-EPMC3113345 | biostudies-literature

Immunodeficiency, centromeric instability, facial anomalies (ICF) syndrome, due to ZBTB24 mutations, presenting with large cerebral cyst.

Project description:The immunodeficiency, centromeric instability, facial anomalies (ICF) syndrome is an autosomal recessive disease presenting with immunodeficiency secondary to hypo- or agamma-globulinemia, developmental delay, and facial anomalies. Centromeric instability is the cytogenetic hallmark of the disorder which results from targeted chromosomal rearrangements related to a genomic methylation defect. We describe a patient carrying a homozygous mutation of the ZBTB24 gene, which has been recently shown to be responsible for ICF syndrome type 2. Our patient presented with intellectual disability, multiple café-au-lait spots, and a large cerebral arachnoidal cyst. Although laboratory signs of impaired immune function, such as reduced serum IgM were detected, our patient did not present clinical manifestations of immunodeficiency. Brain malformations abnormalities have not been reported so far in ICF syndrome and it can be speculated that ZBTB24 mutations may alter cerebral development. Nevertheless, we cannot rule out that the presence of the cerebral cyst in the patient is coincidental. In summary, our patient illustrates that clinical evidence of immunodeficiency is not a universal feature of ICF2 syndrome type 2 and suggests that brain malformations may be present in other ICF cases.

| S-EPMC3402683 | biostudies-literature

Combined immunodeficiency develops with age in Immunodeficiency-centromeric instability-facial anomalies syndrome 2 (ICF2).

Project description:The autosomal recessive immunodeficiency-centromeric instability-facial anomalies syndrome (ICF) is characterized by immunodeficiency, developmental delay, and facial anomalies. ICF2, caused by biallelic ZBTB24 gene mutations, is acknowledged primarily as an isolated B-cell defect. Here, we extend the phenotype spectrum by describing, in particular, for the first time the development of a combined immune defect throughout the disease course as well as putative autoimmune phenomena such as granulomatous hepatitis and nephritis. We also demonstrate impaired cell-proliferation and increased cell death of immune and non-immune cells as well as data suggesting a chromosome separation defect in addition to the known chromosome condensation defect.

| S-EPMC4230835 | biostudies-literature

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

Project description:ICF syndrome is a rare autosomal recessive disorder that is characterized by Immunodeficiency, Centromeric instability, and Facial anomalies. In all, 60% of ICF patients have mutations in the DNMT3B (DNA methyltransferase 3B) gene, encoding a de novo DNA methyltransferase. In ICF cells, constitutive heterochromatin is hypomethylated and decondensed, metaphase chromosomes undergo rearrangements (mainly involving juxtacentromeric regions), and more than 700 genes are aberrantly expressed. This work shows that DNA replication is also altered in ICF cells: (i) heterochromatic genes replicate earlier in the S-phase; (ii) global replication fork speed is higher; and (iii) S-phase is shorter. These replication defects may result from chromatin changes that modify DNA accessibility to the replication machinery and/or from changes in the expression level of genes involved in DNA replication. This work highlights the interest of using ICF cells as a model to investigate how DNA methylation regulates DNA replication in humans.

| S-EPMC3449075 | biostudies-literature

Heterochromatic genes undergo epigenetic changes and escape silencing in immunodeficiency, centromeric instability, facial anomalies (ICF) syndrome.

Project description:Immunodeficiency, Centromeric Instability, Facial Anomalies (ICF) syndrome is a rare autosomal recessive disorder that is characterized by a marked immunodeficiency, severe hypomethylation of the classical satellites 2 and 3 associated with disruption of constitutive heterochromatin, and facial anomalies. Sixty percent of ICF patients have mutations in the DNMT3B (DNA methyltransferase 3B) gene, encoding a de novo DNA methyltransferase. In the present study, we have shown that, in ICF lymphoblasts and peripheral blood, juxtacentromeric heterochromatic genes undergo dramatic changes in DNA methylation, indicating that they are bona fide targets of the DNMT3B protein. DNA methylation in heterochromatic genes dropped from about 80% in normal cells to approximately 30% in ICF cells. Hypomethylation was observed in five ICF patients and was associated with activation of these silent genes. Although DNA hypomethylation occurred in all the analyzed heterochromatic genes and in all the ICF patients, gene expression was restricted to some genes, every patient having his own group of activated genes. Histone modifications were preserved in ICF patients. Heterochromatic genes were associated with histone modifications that are typical of inactive chromatin: they had low acetylation on H3 and H4 histones and were slightly enriched in H3K9Me(3), both in ICF and controls. This was also the case for those heterochromatic genes that escaped silencing. This finding suggests that gene activation was not generalized to all the cells, but rather was restricted to a clonal cell population that may contribute to the phenotypic variability observed in ICF syndrome. A slight increase in H3K27 monomethylation was observed both in heterochromatin and active euchromatin in ICF patients; however, no correlation between this modification and activation of heterochromatic genes was found.

| S-EPMC3084872 | biostudies-literature

Immune Reconstitution after Hematopoietic Stem Cell Transplantation in Immunodeficiency-Centromeric Instability-Facial Anomalies Syndrome Type 1.

Project description: Not available

| S-EPMC7862860 | biostudies-literature

Immunodeficiency, centromeric region instability and facial anomalies (ICF) syndrome diagnosed in an adult who is now a long-term survivor.

Project description:We describe a 42-year-old British man of Indo-Caribbean origin with immunodeficiency, centromeric region instability and facial anomalies (ICF) syndrome. Most patients with ICF syndrome die of infection at a young age, usually in the first or second decade of life. The patient was born 3.5 weeks premature to non-consanguineous parents. He had a mild bird-like face abnormality, but had no other congenital malformations, cognitive impairment or developmental delays. He had recurrent ear and chest infections during childhood and developed bronchiectasis. Investigations revealed IgG, IgA and IgM deficiencies with a normal lymphocyte count and normal T cell proliferation to in vitro mitogenic stimulation. Following several unsuccessful attempts to make a diagnosis during childhood, a recent chromosomal analysis showed centromeric region instability of chromosomes 1 and 16, diagnosing ICF syndrome. The patient receives immunoglobulin replacement for hypogammaglobulinameia and has chest physiotherapy and antibiotics for bronchiectasis. Recently, he developed liver cirrhosis of unknown cause.

| S-EPMC3762531 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data