scholarly journals Cernunnos/XLF Deficiency: A Syndromic Primary Immunodeficiency

2014 ◽  
Vol 2014 ◽  
pp. 1-4 ◽  
Author(s):  
Funda Erol Çipe ◽  
Cigdem Aydogmus ◽  
Arzu Babayigit Hocaoglu ◽  
Merve Kilic ◽  
Gul Demet Kaya ◽  
...  
Keyword(s):  
Primary Immunodeficiency ◽  
Fanconi Anemia ◽  
Growth Retardation ◽  
Perianal Abscess ◽  
Nijmegen Breakage Syndrome ◽  
Homozygous Mutation ◽  
Dna Breaks ◽  
Nbs1 Gene ◽  
Repair Mechanisms ◽  
Severe Growth

Artemis, DNA ligase IV, DNA protein kinase catalytic subunit, and Cernunnos/XLF genes in nonhomologous end joining pathways of DNA repair mechanisms have been identified as responsible for radiosensitive SCID. Here, we present a 3-year-old girl patient with severe growth retardation, bird-like face, recurrent perianal abscess, pancytopenia, and polydactyly. Firstly, she was thought as Fanconi anemia and spontaneous DNA breaks were seen on chromosomal analysis. After that DEB test was found to be normal and Fanconi anemia was excluded. Because of that she had low IgG and IgA levels, normal IgM level, and absence of B cells in peripheral blood; she was considered as primary immunodeficiency, Nijmegen breakage syndrome. A mutation in NBS1 gene was not found; then Cernunnos/XLF deficiency was investigated due to clinical similarities with previously reported cases. Homozygous mutation in Cernunnos/XLF gene (NHEJ1) was identified. She is now on regular IVIG prophylaxis and has no new infection. Fully matched donor screening is in progress for bone marrow transplantation which is curative treatment of the disease. In conclusion, the patients with microcephaly, bird-like face, and severe growth retardation should be evaluated for hypogammaglobulinemia and primary immunodeficiency diseases.

scholarly journals Positioning of nucleosomes containing γ-H2AX precedes active DNA demethylation and transcription initiation

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Stephanie Dobersch ◽  
Karla Rubio ◽  
Indrabahadur Singh ◽  
Stefan Günther ◽  
Johannes Graumann ◽  
...  
Keyword(s):  
Transcription Initiation ◽  
High Mobility ◽  
Dna Demethylation ◽  
High Mobility Group ◽  
Regulation Of Transcription ◽  
Dna Breaks ◽  
Transcriptional Initiation ◽  
High Mobility Group Proteins ◽  
Active Dna Demethylation ◽  
Repair Mechanisms

AbstractIn addition to nucleosomes, chromatin contains non-histone chromatin-associated proteins, of which the high-mobility group proteins are the most abundant. Chromatin-mediated regulation of transcription involves DNA methylation and histone modifications. However, the order of events and the precise function of high-mobility group proteins during transcription initiation remain unclear. Here we show that high-mobility group AT-hook 2 protein (HMGA2) induces DNA nicks at the transcription start site, which are required by the histone chaperone FACT complex to incorporate nucleosomes containing the histone variant H2A.X. Further, phosphorylation of H2A.X at S139 (γ-H2AX) is required for repair-mediated DNA demethylation and transcription activation. The relevance of these findings is demonstrated within the context of TGFB1 signaling and idiopathic pulmonary fibrosis, suggesting therapies against this lethal disease. Our data support the concept that chromatin opening during transcriptional initiation involves intermediates with DNA breaks that subsequently require DNA repair mechanisms to ensure genome integrity.

scholarly journals Pathogenic role of Fgf23 in Dmp1-null mice

2008 ◽  
Vol 295 (2) ◽  
pp. E254-E261 ◽  
Author(s):  
Shiguang Liu ◽  
Jianping Zhou ◽  
Wen Tang ◽  
Rochelle Menard ◽  
Jian Q. Feng ◽  
...  
Keyword(s):  
Growth Retardation ◽  
Matrix Protein ◽  
Serum Levels ◽  
Serum Phosphate ◽  
Hypophosphatemic Rickets ◽  
Null Mouse ◽  
Matrix Mineralization ◽  
Severe Growth ◽  
Inactivating Mutations

Autosomal recessive hypophosphatemic rickets (ARHR), which is characterized by renal phosphate wasting, aberrant regulation of 1α-hydroxylase activity, and rickets/osteomalacia, is caused by inactivating mutations of dentin matrix protein 1 ( DMP1). ARHR resembles autosomal dominant hypophosphatemic rickets (ADHR) and X-linked hypophosphatemia (XLH), hereditary disorders respectively caused by cleavage-resistant mutations of the phosphaturic factor FGF23 and inactivating mutations of PHEX that lead to increased production of FGF23 by osteocytes in bone. Circulating levels of FGF23 are increased in ARHR and its Dmp1-null mouse homologue. To determine the causal role of FGF23 in ARHR, we transferred Fgf23 deficient/enhanced green fluorescent protein (eGFP) reporter mice onto Dmp1-null mice to create mice lacking both Fgf23 and Dmp1. Dmp1−/− mice displayed decreased serum phosphate concentrations, inappropriately normal 1,25(OH)2D levels, severe rickets, and a diffuse form of osteomalacia in association with elevated Fgf23 serum levels and expression in osteocytes. In contrast, Fgf23−/− mice had undetectable serum Fgf23 and elevated serum phosphate and 1,25(OH)2D levels along with severe growth retardation and focal form of osteomalacia. In combined Dmp1−/−/Fgf23−/−, circulating Fgf23 levels were also undetectable, and the serum levels of phosphate and 1,25(OH)2D levels were identical to Fgf23−/− mice. Rickets and diffuse osteomalacia in Dmp1-null mice were transformed to severe growth retardation and focal osteomalacia characteristic of Fgf23-null mice. These data suggest that the regulation of extracellular matrix mineralization by DMP1 is coupled to renal phosphate handling and vitamin D metabolism through a DMP1-dependent regulation of FGF23 production by osteocytes.

scholarly journals CDK10 Mutations in Humans and Mice Cause Severe Growth Retardation, Spine Malformations, and Developmental Delays

2017 ◽  
Vol 101 (3) ◽  
pp. 391-403 ◽  
Author(s):  
Christian Windpassinger ◽  
Juliette Piard ◽  
Carine Bonnard ◽  
Majid Alfadhel ◽  
Shuhui Lim ◽  
...  
Keyword(s):  
Growth Retardation ◽  
Developmental Delays ◽  
Severe Growth

scholarly journals DNA Repair: Exploiting the Fanconi Anemia Pathway As a Potential Therapeutic Target

2011 ◽  
pp. 453-465 ◽  
Author(s):  
T. HUCL ◽  
E. GALLMEIER
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Fanconi Anemia ◽  
Cancer Susceptibility ◽  
Synthetic Lethality ◽  
Bone Marrow Failure ◽  
Long Term Effects ◽  
Alternative Pathways ◽  
Repair Mechanisms ◽  
Relationship Of

DNA repair is an active cellular process to respond to constant DNA damage caused by metabolic processes and environmental factors. Since the outcome of DNA damage is generally adverse and long term effects may contribute to oncogenesis, cells have developed a variety of DNA repair mechanisms, which operate depending on the type of DNA damage inflicted. At least 15 Fanconi anemia (FA) proteins interact in a common pathway involved in homologous recombination. Inherited homozygous mutations in any of these FA genes cause a rare disease, Fanconi anemia, characterized by congenital abnormalities, progressive bone-marrow failure and cancer susceptibility. Heterozygous germline FA mutations predispose to various types of cancer. In addition, somatic FA mutations have been identified in diverse cancer types. Evidence exists that cells deficient in the FA pathway become dependent on alternative pathways for survival. Additional inhibition of such alternative pathways is thus expected to result in cell death, creating a relationship of synthetic lethality. Identifying these relationships can reveal yet unknown mechanisms of DNA repair and new targets for therapy.

scholarly journals Cataract in Seckel Syndrome

1970 ◽  
Vol 13 (1) ◽  
pp. 12-15
Author(s):  
Vinita Girish Rao ◽  
Gunjan Abhijit Deshpande ◽  
Girish Shiva Rao ◽  
Pooja G Rehman
Keyword(s):  
Mental Retardation ◽  
Cataract Surgery ◽  
Short Stature ◽  
Growth Retardation ◽  
In Utero ◽  
Small Incision Cataract Surgery ◽  
Seckel Syndrome ◽  
Bilateral Cataract ◽  
Small Incision ◽  
Severe Growth

Seckel syndrome is an extremely rare inherited disorder characterised by severe growth retardation in utero, which continues later in life, resulting in short stature. Seckel syndrome presents as microcephaly, mental retardation, and a beak-like nose. This report describes a patient with Seckel syndrome who had bilateral cataract and underwent uneventful small incision cataract surgery in both eyes. The association of cataract with Seckel syndrome has not been described in the literature to the best of the authors’ knowledge.

A Bartter syndrome patient presenting with severe growth retardation: Questions

2022 ◽  
Author(s):  
Gökçen Erfidan ◽  
Demet Alaygut ◽  
Özgür Özdemir Şimşek ◽  
Seçil Arslansoyu Çamlar ◽  
Fatma Mutlubaş ◽  
...  
Keyword(s):  
Growth Retardation ◽  
Bartter Syndrome ◽  
Syndrome Patient ◽  
Severe Growth

scholarly journals Canonical and Noncanonical Roles of Fanconi Anemia Proteins: Implications in Cancer Predisposition

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2684 ◽  
Author(s):  
Giacomo Milletti ◽  
Luisa Strocchio ◽  
Daria Pagliara ◽  
Katia Girardi ◽  
Roberto Carta ◽  
...  
Keyword(s):  
Dna Repair ◽  
Fanconi Anemia ◽  
Clinical Phenotype ◽  
Bone Marrow Failure ◽  
Therapeutic Approaches ◽  
Dna Repair Mechanisms ◽  
Solid Malignancies ◽  
Interstrand Cross Links ◽  
Repair Mechanisms ◽  
Cross Links

Fanconi anemia (FA) is a clinically and genetically heterogeneous disorder characterized by the variable presence of congenital somatic abnormalities, bone marrow failure (BMF), and a predisposition to develop cancer. Monoallelic germline mutations in at least five genes involved in the FA pathway are associated with the development of sporadic hematological and solid malignancies. The key function of the FA pathway is to orchestrate proteins involved in the repair of interstrand cross-links (ICLs), to prevent genomic instability and replication stress. Recently, many studies have highlighted the importance of FA genes in noncanonical pathways, such as mitochondria homeostasis, inflammation, and virophagy, which act, in some cases, independently of DNA repair processes. Thus, primary defects in DNA repair mechanisms of FA patients are typically exacerbated by an impairment of other cytoprotective pathways that contribute to the multifaceted clinical phenotype of this disease. In this review, we summarize recent advances in the understanding of the pathogenesis of FA, with a focus on the cytosolic noncanonical roles of FA genes, discussing how they may contribute to cancer development, thus suggesting opportunities to envisage novel therapeutic approaches.

scholarly journals Apoptosis Associated with Deregulated E2F Activity Is Dependent on E2F1 and Atm/Nbs1/Chk2

2004 ◽  
Vol 24 (7) ◽  
pp. 2968-2977 ◽  
Author(s):  
Harry A. Rogoff ◽  
Mary T. Pickering ◽  
Fiona M. Frame ◽  
Michelle E. Debatis ◽  
Yolanda Sanchez ◽  
...  
Keyword(s):  
Ataxia Telangiectasia ◽  
Cellular Proliferation ◽  
Normal Development ◽  
Growth Control ◽  
Nijmegen Breakage Syndrome ◽  
Gene Products ◽  
Apoptosis Induction ◽  
Human Papillomavirus Type 16 ◽  
Nbs1 Gene ◽  
Damage Response

ABSTRACT The retinoblastoma protein (Rb)/E2F pathway links cellular proliferation control to apoptosis and is critical for normal development and cancer prevention. Here we define a transcription-mediated pathway in which deregulation of E2F1 by ectopic E2F expression or Rb inactivation by E7 of human papillomavirus type 16 signals apoptosis by inducing the expression of Chk2, a component of the DNA damage response. E2F1- and E7-mediated apoptosis are compromised in cells from patients with the related disorders ataxia telangiectasia and Nijmegen breakage syndrome lacking functional Atm and Nbs1 gene products, respectively. Both Atm and Nbs1 contribute to Chk2 activation and p53 phosphorylation following deregulation of normal Rb growth control. E2F2, a related E2F family member that does not induce apoptosis, also activates Atm, resulting in phosphorylation of p53. However, we found that the key commitment step in apoptosis induction is the ability of E2F1, and not E2F2, to upregulate Chk2 expression. Our results suggest that E2F1 plays a central role in signaling disturbances in the Rb growth control pathway and, by upregulation of Chk2, may sensitize cells to undergo apoptosis.

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