Immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is a rare autosomal recessive disorder. ICF1 is caused by bi-allelic mutations in the gene encoding deoxyribonucleic ...acid methyltransferase-3B (DNMT3B). Herein, we report a novel homozygous DNMT3B mutation in a patient with ICF1.
An eight-month-old Iranian Caucasian infant of consanguineous 1st-degree cousins presented to our clinic for evaluation of neutropenia. Physical examination was unremarkable except for low-set ears and a systolic cardiac murmur. He had a history of recurrent respiratory infections and oral thrush. Moreover, a collateral artery between the bronchial and pulmonary arteries was observed on the angiogram, mimicking a patent ductus arteriosus on the echocardiogram. Growth percentiles were normal; however, he had a neurodevelopmental delay. Family history was significant for a sibling who deceased at nine months of age after recurrent respiratory infections. Laboratory evaluation revealed a normal white blood cell count with neutropenia and normal bone marrow studies. He had hypogammaglobinemia with normal flow cytometric studies and was treated with prophylactic trimethoprim-sulfamethoxazole and itraconazole. After that, he was re-admitted three times due to recurrent episodes of pneumonia and an episode of pseudomonas aeruginosa meningitis. Currently, he is five years old and doing well on monthly intravenous immunoglobulin. Due to recurrent infections, hypogammaglobulinemia, and neutropenia, as well as a family history of consanguinity and a sibling who deceased during infancy, a primary immune deficiency was suspected. Genetic studies utilizing whole-exome sequencing demonstrated a homozygous missense mutation in DNMT3B (LRG_56t1:c.2008C>T; p.Arg670Trp) in the patient studied. The mutation has not been previously reported.
We describe a novel homozygous DNMT3B mutation in an Iranian boy with ICF1. It is associated with recurrent infections, hypogammaglobinemia, neutropenia, mild facial anomalies, and a bronchopulmonary collateral artery.
Background. Primary ciliary dyskinesia (PCD), also known as the immotile-cilia syndrome, is a clinically and genetically heterogeneous syndrome. Improper function of the cilia causes impaired ...mucociliary clearance. Neonatal respiratory distress, rhinosinusitis, recurrent chest infections, wet cough, and otitis media are respiratory presentations of this disease. It could also manifest as infertility in males as well as laterality defects in both sexes, such as situs abnormalities (Kartagener syndrome). During the past decade, numerous pathogenic variants in 40 genes have been identified as the causatives of primary ciliary dyskinesia. DNAH11 (dynein axonemal heavy chain 11) is a gene that is responsible for the production of cilia’s protein and encodes the outer dynein arm. Dynein heavy chains are motor proteins of the outer dynein arms and play an essential role in ciliary motility. Case Presentation. A 3-year-old boy, the offspring of consanguineous parents, was referred to the pediatric clinical immunology outpatient department with a history of recurrent respiratory tract infections and periodic fever. Furthermore, on medical examination, situs inversus was recognized. His lab results revealed elevated levels of erythrocyte sedimentation rate (ESR) and C reactive protein (CRP). Serum IgG, IgM, and IgA levels were normal, while IgE levels were elevated. Whole exome sequencing (WES) was performed for the patient. WES demonstrated a novel homozygous nonsense variant in DNAH11 (c.5247G > A; p. Trp1749Ter). Conclusion. We reported a novel homozygous nonsense variant in DNAH11 in a 3-year-old boy with primary ciliary dyskinesia. Biallelic pathogenic variants in one of the many coding genes involved in the process of ciliogenesis lead to PCD.
Chemotaxis depends on a network of parallel pathways that coordinate cytoskeletal events to bias cell movement along a chemoattractant gradient. Using a forward genetic screen in Dictyostelium ...discoideum , we identified the Ste20 kinase KrsB, a homolog of tumor suppressors Hippo and MST1/2, as a negative regulator of cell spreading and substrate attachment. The excessive adhesion of krsB ⁻ cells reduced directional movement and prolonged the streaming phase of multicellular aggregation. These phenotypes depended on an intact kinase domain and phosphorylation of a conserved threonine (T176) within the activation loop. Chemoattractants triggered a rapid, transient autophosphorylation of T176 in a heterotrimeric G protein-dependent and PI3K- and TorC2-independent manner. The active phosphorylated form of KrsB acts to decrease adhesion to the substrate. Taken together these studies suggest that cycling between active and inactive forms of KrsB may provide the dynamic regulation of cell adhesion needed for proper cell migration and chemotaxis. KrsB interacts genetically with another D. discoideum Hippo/MST homolog, KrsA, but the two genes are not functionally redundant. These studies show that Hippo/MST proteins, like the tumor suppressor PTEN and oncogenes Ras and PI3K, play a key role in cell morphological events in addition to their role in regulating cell growth.
The human ENaC (epithelial sodium channel), a complex of three subunits, provides the rate-limiting step for sodium uptake in the distal nephron, and therefore plays a key role in salt homoeostasis ...and in regulating blood pressure. The number of active sodium channel complexes present at the plasma membrane appears to be tightly controlled. In Liddle's syndrome, a form of hypertension caused by an increase in the number of active sodium channels at the cell membrane, the betaENaC or gammaENaC subunit gene contains a mutation that disrupts the binding site for the Nedd4 (neuronal precursor cell expressed developmentally down-regulated gene 4) family of ubiquitin-protein ligases. Therefore ubiquitination of channel subunits may be involved in altering cell surface ENaC. Here, we provide evidence that the ENaC subunits located at the cell surface are modified with multiple mono-ubiquitins (multi-ubiquitination) and that Nedd4-2 modulates this ubiquitination. We confirm that ENaC is associated with the mu2 subunit of the AP-2 (adaptor protein 2) clathrin adaptor. Since mono- or multi-ubiquitination of other membrane proteins is a signal for their internalization by clathrin-mediated endocytosis and subsequent trafficking, our results support a model whereby ubiquitin and clathrin adaptor binding sites act in concert to remove ENaC from the cell surface.
Chronic active Epstein-Barr virus (EBV) infection (CAEBV) is an EBV-associated lymphoproliferative disease characterized by repeated or sustainable infectious mononucleosis (IM)-like symptoms. EBV is ...usually detected in B cells in patients who have IM or Burkitt's lymphoma and even in patients with X-linked lymphoproliferative syndrome, which is confirmed to have vulnerability to EBV infection. In contrast, EBV infects T cells (CD4
T, CD8
T, and γδT) or NK cells mono- or oligoclonally in CAEBV patients. It is known that the CAEBV phenotypes differ depending on which cells are infected with EBV. CAEBV is postulated to be associated with a genetic immunological abnormality, although its cause remains undefined. Here we describe a case of EBV-related γδT-cell proliferation with underlying hypomorphic
mutation. The immunological phenotype consisted of γδT-cell proliferation in the peripheral blood. A presence of EBV-infected B cells and γδT cells mimicked γδT-cell-type CAEBV. Although the patient had normal expression of CD132 (common γ chain), the phosphorylation of STAT was partially defective, indicating impaired activation of the downstream signal of the JAK/STAT pathway. Although the patient was not diagnosed as having CAEBV, this observation shows that CAEBV might be associated with immunological abnormality.
Actin belongs to the most abundant proteins in eukaryotic cells which harbor usually many conventional actin isoforms as well as actin-related proteins (Arps). To get an overview over the sometimes ...confusing multitude of actins and Arps, we analyzed the Dictyostelium discoideum actinome in detail and compared it with the genomes from other model organisms. The D. discoideum actinome comprises 41 actins and actin-related proteins. The genome contains 17 actin genes which most likely arose from consecutive gene duplications, are all active, in some cases developmentally regulated and coding for identical proteins (Act8-group). According to published data, the actin fraction in a D. discoideum cell consists of more than 95% of these Act8-type proteins. The other 16 actin isoforms contain a conventional actin motif profile as well but differ in their protein sequences. Seven actin genes are potential pseudogenes. A homology search of the human genome using the most typical D. discoideum actin (Act8) as query sequence finds the major actin isoforms such as cytoplasmic beta-actin as best hit. This suggests that the Act8-group represents a nearly perfect actin throughout evolution. Interestingly, limited data from D. fasciculatum, a more ancient member among the social amoebae, show different relationships between conventional actins. The Act8-type isoform is most conserved throughout evolution. Modeling of the putative structures suggests that the majority of the actin-related proteins is functionally unrelated to canonical actin. The data suggest that the other actin variants are not necessary for the cytoskeleton itself but rather regulators of its dynamical features or subunits in larger protein complexes.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Emerging immunotherapies such as chimeric antigen receptor T cells have advanced the treatment of acute lymphoblastic leukemia. In contrast, long-term control of acute myeloid leukemia (AML) cannot ...be achieved by single lineage-specific targeting while sparing benign hematopoiesis. In addition, heterogeneity of AML warrants combinatorial targeting, and several suitable immunotargets (HAVCR2/CD33 and HAVCR2/CLEC12A) have been identified in adult AML. However, clinical and biologic characteristics of AML differ between children and the elderly. Here, we analyzed 36 bone marrow (BM) samples of pediatric AML patients and 13 age-matched healthy donors using whole RNA sequencing of sorted CD45dim and CD34+CD38−CD45dim BM populations and flow cytometry for surface expression of putative target antigens. Pediatric AML clusters apart from healthy myeloid BM precursors in principal-component analysis. Known immunotargets of adult AML, such as IL3RA, were not overexpressed in pediatric AML compared with healthy precursors by RNA sequencing. CD33 and CLEC12A were the most upregulated immunotargets on the RNA level and showed the highest surface expression on AML detected by flow cytometry. KMT2A-mutated infant AML clusters separately by RNA sequencing and overexpresses FLT3, and hence, CD33/FLT3 cotargeting is an additional specific option for this subgroup. CLEC12A and CD33/CLEC12Adouble-positive expression was absent in CD34+CD38−CD45RA−CD90+ hematopoietic stem cells (HSCs) and nonhematopoietic tissue, while CD33 and FLT3 are expressed on HSCs. In summary, we show that expression of immunotargets in pediatric AML differs from known expression profiles in adult AML. We identify CLEC12A and CD33 as preferential generic combinatorial immunotargets in pediatric AML and CD33 and FLT3 as immunotargets specific for KMT2A-mutated infant AML.
•Expression of target molecules for pediatric AML immunotherapy differs from expression profiles in adult AML.•CD33/CLEC12A are preferential generic pediatric AML combinatorial immunotargets, and CD33/FLT3 are specific to KMT2A-mutated infant AML.
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Severe Reduction in All Serum Immunoglobulin Isotypes with Profoundly Decreased or Absent B Cells is a subgroup of inborn error of immunities (IEI). 80 to 90% carry mutations in X-chromosomal Bruton ...tyrosine kinase (BTK) and around 5–10% of the cases are autosomal recessive Agammaglobulinemia (ARA). Very few of Hypogammaglobulinemia with no B cells classified in other subgroups. All of these patients benefit from a genetic evaluation, especially in highly consanguine populations.
27 patients from 11 families with hypogamma-globinemia and no B-cells registered in Immunodeficiency Diseases Research Center registry, Isfahan University of Medical Sciences were phenotypically and genetically evaluated.
The most prevalent genetic cause was mutations in BTK. The novel mutations in BTK gene includes c.176 G>A (p. Glu89Lys); c.115T>C (p. Tyr39His); c.685-686insTTAC (p. Asn229llefs5), in ARA includes a homozygous stop mutation in Immunoglobulin Heavy Constant Mu Chain (IGHM) gene, a frameshift mutation of B-Cell Antigen Receptor Complex-Associated Protein (CD79A), a bi-allelic stop-gain mutation in Transcription Factor 3 (TCF3), and in PIK3CD also in others IEI includes :novel homozygous silent mutations in Phosphoinositide-3-Kinase Regulatory Subunit (RASGRP1), homozygote SAMD9 mutation.
We did not observe any phenotypically significant differences in XLA patients.
The main clinical manifestation of ARA cases is, recurrent infections. However, patient with IGHM deficiency had earlier onset of the disease and more severe complications. In CD79A deficient case with 5 affected members and four deaths in her family, the symptoms started very early but managed properly according to the family history. Due to the late diagnosis of PIK3CD cases, more severe complications like bronchiectasis, neurologic sequels after poliomyelitis, and SLE nephropathy has been developed. Our novel SAMD9 had quite different phenotype and the novel RASPGR2 case with no B cells unfortunately managed as ARA before genetic diagnosis and has died of lymphoma as her 3 siblings. However, we observed that in families with more than one affected family member, the disease was better controlled in the second patient.
Our study broadens the genetic spectrum of hypogammaglobulinemia with no B cells in Iran. This helps differentiate phenotypes and genotypes and manage patients appropriately.
Hypogammaglobulinemia without B-cells is a subgroup of inborn errors of immunity (IEI) which is characterized by a significant decline in all serum immunoglobulin isotypes, coupled with a pronounced ...reduction or absence of B-cells. Approximately 80 to 90% of individuals exhibit genetic variations in Bruton’s agammaglobulinemia tyrosine kinase (BTK), whereas a minority of cases, around 5–10%, are autosomal recessive agammaglobulinemia (ARA). Very few cases are grouped into distinct subcategories. We evaluated phenotypically and genetically 27 patients from 13 distinct families with hypogammaglobinemia and no B-cells. Genetic analysis was performed via whole-exome and Sanger sequencing. The most prevalent genetic cause was mutations in
BTK
. Three novel mutations in the
BTK
gene include c.115 T > C (p. Tyr39His), c.685-686insTTAC (p.Asn229llefs5), and c.163delT (p.Ser55GlnfsTer2). Our three ARA patients include a novel homozygous stop-gain mutation in the immunoglobulin heavy constant Mu chain (
IGHM
) gene, a novel frameshift mutation of the B-cell antigen receptor complex-associated protein (
CD79A
) gene, a novel bi-allelic stop-gain mutation in the transcription factor 3 (
TCF3
) gene. Three patients with agammaglobulinemia have an autosomal dominant inheritance pattern, which includes a missense variant in
PIK3CD
, a novel missense variant in
PIK3R1
and a homozygous silent mutation in the phosphoinositide-3-kinase regulatory subunit (
RASGRP1
) gene. This study broadens the genetic spectrum of hypogammaglobulinemia without B-cells and presented a few novel variants within the Iranian community, which may also have implications in other Middle Eastern populations. Notably, disease control was better in the second affected family member in families with multiple cases.
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