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.

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CDCA7 and HELLS suppress DNA:RNA hybrid-associated DNA damage at pericentromeric repeats

Scientific Reports ◽

10.1038/s41598-020-74636-2 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Motoko Unoki ◽

Jafar Sharif ◽

Yuichiro Saito ◽

Guillaume Velasco ◽

Claire Francastel ◽

...

Keyword(s):

Dna Damage ◽

Autosomal Recessive ◽

Ectopic Expression ◽

Autosomal Recessive Disorder ◽

End Joining ◽

Icf Syndrome ◽

Centromeric Instability ◽

Non Homologous End Joining ◽

Genomic Regions ◽

Mutant Cells

Abstract Immunodeficiency, centromeric instability, facial anomalies (ICF) syndrome is a rare autosomal recessive disorder that is caused by mutations in either DNMT3B, ZBTB24, CDCA7, HELLS, or yet unidentified gene(s). Previously, we reported that the CDCA7/HELLS chromatin remodeling complex facilitates non-homologous end-joining. Here, we show that the same complex is required for the accumulation of proteins on nascent DNA, including the DNMT1/UHRF1 maintenance DNA methylation complex as well as proteins involved in the resolution or prevention of R-loops composed of DNA:RNA hybrids and ssDNA. Consistent with the hypomethylation state of pericentromeric repeats, the transcription and formation of aberrant DNA:RNA hybrids at the repeats were increased in ICF mutant cells. Furthermore, the ectopic expression of RNASEH1 reduced the accumulation of DNA damage at a broad range of genomic regions including pericentromeric repeats in these cells. Hence, we propose that hypomethylation due to inefficient DNMT1/UHRF1 recruitment at pericentromeric repeats by defects in the CDCA7/HELLS complex could induce pericentromeric instability, which may explain a part of the molecular pathogenesis of ICF syndrome.

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DNA methyltransferase 3B mutations linked to the ICF syndrome cause dysregulation of lymphogenesis genes

Human Molecular Genetics ◽

10.1093/hmg/10.25.2917 ◽

2001 ◽

Vol 10 (25) ◽

pp. 2917-2931 ◽

Cited By ~ 86

Author(s):

M. Ehrlich

Keyword(s):

Dna Methyltransferase ◽

Icf Syndrome ◽

Dna Methyltransferase 3B

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Macrophage Activation Syndrome Mimicking Life-Threatening Infection in a Patient With Variable Immunodeficiency, Centromeric Instability, and Facial Anomalies

PEDIATRICS ◽

10.1542/peds.2004-1271 ◽

2004 ◽

Vol 114 (4) ◽

pp. 1127-1127 ◽

Cited By ~ 4

Author(s):

N. Andre

Keyword(s):

Macrophage Activation Syndrome ◽

Macrophage Activation ◽

Facial Anomalies ◽

Life Threatening ◽

Centromeric Instability ◽

Activation Syndrome

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ICF syndrome (immunodeficiency, centromeric instability and facial anomalies): investigation of heterochromatin abnormalities and review of clinical outcome

Human Genetics ◽

10.1007/bf00191798 ◽

1995 ◽

Vol 96 (4) ◽

Cited By ~ 42

Author(s):

DonaldC. Brown ◽

Elizabeth Grace ◽

AdrianT. Sumner ◽

A.Trevor Edmunds ◽

PatriciaM. Ellis

Keyword(s):

Clinical Outcome ◽

Icf Syndrome ◽

Facial Anomalies ◽

Centromeric Instability

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Immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome with NK dysfunction and EBV-driven malignancy treated with stem cell transplantation

The Journal of Allergy and Clinical Immunology In Practice ◽

10.1016/j.jaip.2019.08.040 ◽

2020 ◽

Vol 8 (3) ◽

pp. 1103-1106.e3 ◽

Cited By ~ 2

Author(s):

Caitlin M. Burk ◽

Kara E. Coffey ◽

Emily M. Mace ◽

Bret L. Bostwick ◽

Ivan K. Chinn ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Icf Syndrome ◽

Facial Anomalies ◽

Centromeric Instability

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Clinical, Immunologic, and Molecular Spectrum of Patients with Immunodeficiency, Centromeric instability, and Facial anomalies (ICF) syndrome: a Systematic Review

Endocrine Metabolic & Immune Disorders - Drug Targets ◽

10.2174/1871530320666200613204426 ◽

2020 ◽

Vol 20 ◽

Author(s):

Fatemeh Kiaee ◽

Majid Zaki-Dizaji ◽

Nasim Hafezi ◽

Amir Almasi-Hashiani ◽

Haleh Hamedifar ◽

...

Keyword(s):

Motor Development ◽

Fungal Infections ◽

Disease Free Survival ◽

Failure To Thrive ◽

Facial Dysmorphism ◽

Chronic Infections ◽

Immune Disorder ◽

Icf Syndrome ◽

Facial Anomalies ◽

Centromeric Instability

Background: Immunodeficiency, centromeric instability and facial dysmorphism )ICF) syndrome is a rare autosomal recessive immune disorder presenting with hypogammaglobulinemia, developmental delay, and facial anomalies. The ICF type 1, type 2, type 3 and type 4 are characterized by mutations in DNMT3B, ZBTB24, CDCA7 or HELLS gene, respectively. This study aimed to present a comprehensive description of the clinical, immunologic and genetic features of patients with ICF syndrome. Methods: PubMed, Web of Science, and Scopus were searched systemically to find eligible studies. Results: Forty-eight studies with 118 ICF patients who met the inclusion criteria were included in our study. Among these patients, 60% reported with ICF-1, 30% with ICF-2, 4% with ICF-3, and 6% with ICF-4. The four most common symptoms reported in patients with ICF syndrome were: delay in motor development, low birth weight, chronic infections, and diarrhea. Intellectual disability and preterm birth among patients with ICF-2 and failure to thrive, sepsis and fungal infections among patients with ICF-1 were also more frequent. Moreover, the median levels of all three immunoglobulins (IgA, IgG, IgM) were markedly reduced within four types of ICF syndrome. Conclusion: The frequency of diagnosed patients with ICF syndrome has increased. Early diagnosis of ICF is important since immunoglobulin supplementation or allogeneic stem cell transplantation can improve the disease-free survival rate.

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Fanconi anemia

Bangladesh Medical Journal Khulna ◽

10.3329/bmjk.v50i1-2.35844 ◽

2018 ◽

Vol 50 (1-2) ◽

pp. 46-48

Author(s):

Forrukh Ahammad ◽

Habiba Sultana Rupa ◽

AKM Mamunur Rashid ◽

Choudhury Habibur Rasul

Keyword(s):

Fanconi Anemia ◽

Gold Standard ◽

Autosomal Recessive ◽

Autosomal Recessive Disorder ◽

Preventive Strategy ◽

Chromosome Break ◽

Multiple Congenital Anomalies ◽

Life Threatening ◽

Progressive Pancytopenia ◽

Multiple Type

Fanconi Anemia (FA) is a rare potentially life threatening autosomal recessive disorder characterized by progressive pancytopenia, multiple congenital anomalies with multiple type of cancer risk. The presentation may be variable but typical presentation make the diagnosis easy. Diagnosis of FA can be confirmed by chromosome break study which is regarded as the gold standard diagnostic test for FA. Only one case report of FA had been published from Bangladesh till now. Here is the second variety of FA. If FA is confirmed then a set of preventive strategy can be applied. On the other hand misdiagnosis may lead to mismanagement which is not uncommon.Bang Med J (Khulna) 2017; 50 : 46-48

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Three Types of Immunodeficiency, Centromeric Instability, and Facial Anomalies (ICF) Syndrome Identified by Whole-Exome Sequencing in Saudi Hypogammaglobulinemia Patients: Clinical, Molecular, and Cytogenetic Features

Journal of Clinical Immunology ◽

10.1007/s10875-018-0569-9 ◽

2018 ◽

Vol 38 (8) ◽

pp. 847-853 ◽

Cited By ~ 6

Author(s):

Hamza A. Alghamdi ◽

Suha A. Tashkandi ◽

Eman M. Alidrissi ◽

Rawan D. Aledielah ◽

Khelad A. AlSaidi ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Icf Syndrome ◽

Facial Anomalies ◽

Whole Exome ◽

Centromeric Instability

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Loss of ZBTB24 impairs nonhomologous end-joining and class-switch recombination in patients with ICF syndrome

Journal of Experimental Medicine ◽

10.1084/jem.20191688 ◽

2020 ◽

Vol 217 (11) ◽

Cited By ~ 2

Author(s):

Angela Helfricht ◽

Peter E. Thijssen ◽

Magdalena B. Rother ◽

Rashmi G. Shah ◽

Likun Du ◽

...

Keyword(s):

Autosomal Recessive ◽

Class Switch Recombination ◽

Nonhomologous End Joining ◽

Dna Breaks ◽

End Joining ◽

Immunoglobulin Production ◽

Icf Syndrome ◽

Class Switch ◽

Centromeric Instability ◽

Gene Defects

The autosomal recessive immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is a genetically heterogeneous disorder. Despite the identification of the underlying gene defects, it is unclear how mutations in any of the four known ICF genes cause a primary immunodeficiency. Here we demonstrate that loss of ZBTB24 in B cells from mice and ICF2 patients affects nonhomologous end-joining (NHEJ) during immunoglobulin class-switch recombination and consequently impairs immunoglobulin production and isotype balance. Mechanistically, we found that ZBTB24 associates with poly(ADP-ribose) polymerase 1 (PARP1) and stimulates its auto-poly(ADP-ribosyl)ation. The zinc-finger in ZBTB24 binds PARP1-associated poly(ADP-ribose) chains and mediates the PARP1-dependent recruitment of ZBTB24 to DNA breaks. Moreover, through its association with poly(ADP-ribose) chains, ZBTB24 protects them from degradation by poly(ADP-ribose) glycohydrolase (PARG). This facilitates the poly(ADP-ribose)-dependent assembly of the LIG4/XRCC4 complex at DNA breaks, thereby promoting error-free NHEJ. Thus, we uncover ZBTB24 as a regulator of PARP1-dependent NHEJ and class-switch recombination, providing a molecular basis for the immunodeficiency in ICF2 syndrome.

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