Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The recessive ataxia-telangiectasia (A-T) syndrome is characterized by cerebellar degeneration, immunodeficiency, cancer susceptibility, premature aging, and insulin-resistant diabetes and is caused by loss of function of the ATM kinase, a member of the phosphoinositide 3-kinase-like protein kinases (PIKKs) family. ATM plays a crucial role in the DNA damage response (DDR); however, the complexity of A-T features suggests that ATM may regulate other cellular functions. Here we show that ATM affects proper bipolar mitotic spindle structure independently of DNA damage. In addition, we find that in mitosis ATM forms a complex with the poly(ADP)ribose (PAR) polymerase Tankyrase (TNKS) 1, the spindle pole protein NuMA1, and breast cancer susceptibility protein BRCA1, another crucial DDR player. Our evidence indicates that the complex is required for efficient poly(ADP)ribosylation of NuMA1. We find further that a mutant NuMA1 version, non-phosphorylatable at potential ATM-dependent phosphorylation sites, is poorly PARylated and induces loss of spindle bipolarity. Our findings may help to explain crucial A-T features and provide further mechanistic rationale for TNKS inhibition in cancer therapy.
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PMID:ATM controls proper mitotic spindle structure. 2455 24

Genome-wide RNA interference screens have greatly facilitated the identification of essential host factors (EHFs) for viral infections, whose knockdown effects significantly influence virus replication but not host cell viability. However, little has been done to link EHFs with another important host factor type, i.e., virus targeting proteins (VTPs) that viruses directly interact with for intracellular survival, hampering the integrative understanding of virus-host interactions. Using EHFs and VTPs for human immunodeficiency virus type 1 (HIV-1) and influenza A virus (IAV) infections, we found in general that despite limited overlap, EHFs and VTPs are both among the most differentially dysregulated genes in host transcriptional response to HIV and IAV infections, and notably they show consistency in regulation orientation. In the human protein-protein interaction network, both EHFs and VTPs hold topologically important positions at the global center, and importantly their direct interactions are statistically significant. We also identified BRCA1 and TP53 (or SMAD3 and PIK3R1) being the most extensive VTP-interacting EHFs (or EHF-interacting VTPs) for HIV-1 and IAV, which hold great potential in deciphering specific infection features and discovery of host directed antivirals. Further, most EHFs are the upstream regulators of VTPs when mapped in the same signaling pathways, some of which present intensive cross links. Collectively, these results provide insights into functional associations of the identified host gene factors for viral infections and highlight the regulatory significance of EHFs, and the necessity of their selective exploitation in confrontation to viral infections.
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PMID:Exploring the associations of host genes for viral infection revealed by genome-wide RNAi and virus-host protein interactions. 2616 90

Background: Common variable immunodeficiency disorder (CVID) is one of the most frequent inborn errors of immunity, increased occurrence of malignancies, particularly lymphomas, and gastric cancers, has long been noted among CVID patients. Multifactorial etiology, including immune dysregulation, infections, chronic inflammation, or genetic background, is suggested to contribute to tumor development. Here, we present the results of the first Czech nationwide study focused on epidemiology, immunology and genetic background in a cohort of CVID patients who also developed tumors Methods: The cohort consisted of 295 CVID patients followed for 3,070 patient/years. Standardized incidence ratio (SIR) was calculated to determine the risk of cancer, and Risk ratio (RR) was established to evaluate the significance of comorbidities. Moreover, immunophenotyping, including immunoglobulin levels and lymphocyte populations, was assessed. Finally, Whole exome sequencing (WES) was performed in all patients with lymphoma to investigate the genetic background. Results: Twenty-five malignancies were diagnosed in 22 patients in a cohort of 295 CVID patients. SIR was more than 6 times greater in comparison to the general population. The most common neoplasias were gastric cancers and lymphomas. History of Immune thrombocytopenic purpura (ITP) was established as a potential risk factor, with over 3 times higher risk of cancer development. The B cell count at diagnosis of lymphoma was reduced in the lymphoma group; moreover, post-treatment B and T cell lymphopenia, associated with poorer outcome, was found in a majority of the patients. Intriguingly, no NK cell depression was observed after the chemotherapy. WES revealed heterogeneous genetic background among CVID patients with tumors, identifying gene variants associated with primary immunodeficiencies (such as CTLA4, PIK3CD, PMS2) and/or increased cancer susceptibility (including BRCA1, RABEP1, EP300, KDM5A). Conclusions: The incidence of malignancy in our CVID cohort was found to be more than 6 times greater compared to the general population. Gastric cancers and lymphomas were the most frequently diagnosed tumors. ITP was identified as a risk factor for malignancy in CVID patients. WES analysis confirmed a wide genetic heterogeneity among CVID patients. The identified causative or modifying gene variants pointed to errors in mechanisms contributing to both immunodeficiency and malignancy.
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PMID:CVID-Associated Tumors: Czech Nationwide Study Focused on Epidemiology, Immunology, and Genetic Background in a Cohort of Patients With CVID. 3072 78

The current debate and policy surrounding the use of genome editing in humans typically relies on a binary distinction between therapy and human enhancement. Here, we argue that this dichotomy fails to take into account perhaps the most significant potential uses of CRISPR-Cas9 genome editing in humans. We argue that genetic treatment of sporadic Alzheimer's disease, breast and ovarian cancer predisposing BRCA1/2 mutations, and the introduction of human immunodeficiency virus resistance in humans should be considered within a new category of genetic protection treatments. We suggest that if this category is not introduced, life-altering research might be unnecessarily limited by current or future policy. Otherwise ad hoc decisions might be made, which introduce a risk of unforeseen moral costs, and might overlook or fail to address some important opportunities.
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PMID:Genetic Protection Modifications: Moving Beyond the Binary Distinction Between Therapy and Enhancement for Human Genome Editing. 3186 Mar 50

A 43 -year-old woman presented to the hospital with a right breast tumor. She had been treated for human immunodeficiency virus(HIV)infection for 5 years. After being diagnosed with right breast cancer, she underwent total mastectomy and sentinel lymph node biopsy, which indicated T2N1M0 triple-negative breast cancer. She received doxorubicin and cyclophosphamide( AC)followed by docetaxel(AC-T)as postoperative adjuvant chemotherapy. However, 14 months after the adjuvant chemotherapy finished, distant metastasis occurred in the brain, lung, and mediastinum lymph nodes. Treatment for relapse was initiated, with whole brain radiotherapy followed by paclitaxel plus bevacizumab combination therapy(PB); however, new metastatic lesions were found in the bone, liver, and mediastinum lymph node after 2 courses of PB. Given the risk of hereditary breast and ovarian cancer syndrome, a BRCAgene test was performed when the patient received radiotherapy for left recurrent laryngeal nerve paralysis caused by mediastinal lymph nodes; this showed a result positive for a deleterious mutation in BRCA1. Thus, treatment with olaparib, a poly(ADP-ribose)polymerase(PARP)inhibitor, was started. Metastatic lesions, including barky growth, in the liver metastasis were well controlled, as confirmed by CT imaging 4 months after the start of olaparib.
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PMID:[A Case Report on the Effectiveness of Olaparib in a Patient with Recurrent Breast Cancer with Human Immunodeficiency Virus Infection]. 3266 58

Pathogenic variants in BRCA1 gene in heterozygous state are known to be associated with breast-ovarian cancer susceptibility; however, biallelic variants cause a phenotype recognised as Fanconi anaemia complementation group S. Due to its rarity, medical management and preventive screening measures are insufficiently understood. Here, we present nine individuals (one new and eight previously presented) with biallelic variants in BRCA1 gene, to delineate clinical features in comparison with other chromosome instability syndromes and understand the patients' health risk. Features seen in these 9 individuals (7 females/2 males) include prenatal and postnatal growth failure (9/9), microcephaly (9/9), hypo/hyperpigmented lesions (9/9), facial dysmorphism (9/9), mild developmental delay (8/9) and early-onset solid tumours (5/9). None presented bone marrow failure or immunodeficiency. Individuals with biallelic variants in BRCA1 also showed chromosomal instability by mitomycin and diepoxybutane test. The phenotype caused by biallelic BRCA1 variants is best framed between Fanconi anaemia and Nijmegen syndrome, yet distinct due to lack of bone marrow failure and immunodeficiency. We hypothesise that disease class should be reframed and medical management in people with biallelic variants in BRCA1 should emphasise on detection of solid tumour development and avoiding exposure to ionising radiation.
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PMID:Biallelic variants in BRCA1 gene cause a recognisable phenotype within chromosomal instability syndromes reframed as BRCA1 deficiency. 3284 87


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