CRISPR/Cas9 Mediated ELANE Knock-out Restores Survival and Granulocytic Differentiation of HL60 Cells Expressing Mutant Neutrophil Elastase: Is Neutrophil Elastase a Dispensible Granulocyte Protease?
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Congenital Neutropenia
Neutrophil elastase
Introduction: Severe congenital neutropenia (SCN) includes a group of genetic disorders which cause to arrest of neutrophil maturation. SCN can be associated with heterogenous group of genetic defects in ELANE, GFI1, HAX1, G6PC3, JAGN1, VPS45 or activating mutations in the Wiskott-Aldrich syndrome (WAS) gene. Aim: Here we report a patient who has a HAX1 mutation presented with cyclic manner. Case Report: A 6 year old female patients was admitted with recurrent apthous stomatitis. We followed the patient as cyclic neutropenia according to complete blood count results 2 times for 6 weeks. After persistant neutropenia developed during a severe varicella infection, we analysed HAX1 mutation, the result was interesting and incompatible with reported cyclic neutropenia patients. Conclusion: We suggest that HAX1 deficiency should be thought in patients who have normal neutrophil counts in the between of infections.
Congenital Neutropenia
Cyclic neutropenia
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Neutropenia is common in the practice of both primary care physicians and physicians of sub-speciality. Congenital neutropenia are rare diseases; they can be both isolated independent diseases and accompany a number of other inborn errors of immunity. The clinical course of neutropenia can range from asymptomatic in patients with mild neutropenia to life-threatening infections in cases of severe neutropenia. Treatment of congenital neutropenia remains discutable to this day. The most common and accessible method of treatment of severe congenital neutropenia is granulocyte colony-stimulating factor, although it does not cure the disease and does not prevent the development of malignant transformation. On the other hand, the use of granulocyte colony-stimulating factor in the correct doses can improve the clinical course of the disease, the quality of life of patients, avoid severe septic complications. Hematopoietic stem cell transplant is an effective treatment for severe congenital neutropenia that does not respond to granulocyte colony-stimulating factor therapy. Modern methods of genetic therapy open new perspectives in the treatment of patients with severe congenital neutropenia. No conflict of interests was declared by the author. Key words: congenital neutropenia, treatment, Granulocyte colony-stimulating factor (G-CSF).
Congenital Neutropenia
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Congenital Neutropenia
Cyclic neutropenia
Absolute neutrophil count
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Congenital neutropenia, which refers to an inherited deficiency in neutrophils, is a rare pathologic condition that affects approximately 0.0001-0.0009% of the general population. While congenital neutropenia can result from mutations in approximately 30 genes, its leading cause is gain-of-function mutations in the ELANE gene, which encodes the neutrophil granule serine protease, neutrophil elastase. This review focuses on established and novel concepts in the genetic, molecular and cellular mechanisms underlying neutrophil elastase-dependent neutropenia, and discusses possible new avenues for neutropenia research as well as potential novel treatment options that target pathogenic elastase variants.
Congenital Neutropenia
Neutrophil elastase
Cyclic neutropenia
Neutrophil Extracellular Traps
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Severe congenital neutropenia (SCN) is a rare hematological condition with heterogenous genetic background. Neutrophil elastase (NE) encoded by ELANE gene is mutated in over half of the SCN cases. The role of NE defects in myelocytes maturation arrest in bone marrow is widely investigated; however, the mechanism underlying this phenomenon has still remained unclear. In this review, we sum up the studies exploring mechanisms of neutrophil deficiency, biological role of NE in neutrophil and the effects of ELANE mutation and neutropenia pathogenesis. We also explain the hypotheses presented so far and summarize options of neutropenia therapy.
Congenital Neutropenia
Neutrophil elastase
Cyclic neutropenia
Pathogenesis
Neutrophil Extracellular Traps
Absolute neutrophil count
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Abstract Congenital neutropenia comprises a variety of genetically heterogeneous phenotypic traits. Molecular elucidation of the underlying genetic defects has yielded important insights into the physiology of neutrophil differentiation and function. Non-syndromic variants of congenital neutropenia are caused by mutations in ELA2, HAX1, GFI1, or WAS. Syndromic variants of congenital neutropenia may be due to mutations in genes controlling glucose metabolism (SLC37A4, G6PC3) or lysosomal function (LYST, RAB27A, ROBLD3/p14, AP3B1, VPS13B). Furthermore, defects in genes encoding ribosomal proteins (SBDS, RMRP) and mitochondrial proteins (AK2, TAZ) are associated with congenital neutropenia syndromes. Despite remarkable progress in the field, many patients with congenital neutropenia cannot yet definitively be classified by genetic terms. This review addresses diagnostic and therapeutic aspects of congenital neutropenia and covers recent molecular and pathophysiological insights of selected congenital neutropenia syndromes.
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Cyclic neutropenia
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Congenital Neutropenia
Pathophysiology
Cyclic neutropenia
Genetic syndromes
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The main features of severe congenital neutropenia are the onset of severe bacterial infections early in life, a paucity of mature neutrophils, and an increased risk of leukemia. In many patients, the genetic causes of severe congenital neutropenia are unknown.We performed genomewide genotyping and linkage analysis on two consanguineous pedigrees with a total of five children affected with severe congenital neutropenia. Candidate genes from the linkage interval were sequenced. Functional assays and reconstitution experiments were carried out.All index patients were susceptible to bacterial infections and had very few mature neutrophils in the bone marrow; structural heart defects, urogenital abnormalities, and venous angiectasia on the trunk and extremities were additional features. Linkage analysis of the two index families yielded a combined multipoint lod score of 5.74 on a linkage interval on chromosome 17q21. Sequencing of G6PC3, the candidate gene encoding glucose-6-phosphatase, catalytic subunit 3, revealed a homozygous missense mutation in exon 6 that abolished the enzymatic activity of glucose-6-phosphatase in all affected children in the two families. The patients' neutrophils and fibroblasts had increased susceptibility to apoptosis. The myeloid cells showed evidence of increased endoplasmic reticulum stress and increased activity of glycogen synthase kinase 3beta (GSK-3beta). We identified seven additional, unrelated patients who had severe congenital neutropenia with syndromic features and distinct biallelic mutations in G6PC3.Defective function of glucose-6-phosphatase, catalytic subunit 3, underlies a severe congenital neutropenia syndrome associated with cardiac and urogenital malformations.
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Cyclic neutropenia
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Congenital Neutropenia
Cyclic neutropenia
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The term congenital neutropenia embrace a family neutropenic disorders, that can be permanent or intermittent, severe or pleasant, which can cause repercussions in other organ systems. Neutropenia can range from mild pyogenic infections to life-threatening sepsis, and each successive infection can leave permanent sequelae. The risk of infection is approximately inversely proportional to the circulating polymorphonuclear neutrophil count and is particularly high at counts below 0.2G/l. About half of the forms of congenital neutropenia, without extrahematopoietic manifestations and normal adaptive immunity, are due to mutations in neutrophil elastase. Some patients have severe permanent neutropenia and frequent infections early in life, while others have mild intermittent neutropenia. The difficulty in suspected diagnosis congenital neutropenia and, consequently, the time to start treatment can lead to infectious complications and put the patients’ life at risk.
Congenital Neutropenia
Absolute neutrophil count
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