The clinical, immunohematological, and molecular study of Iranian patients with severe congenital neutropenia.
ABSTRACT Severe congenital neutropenia (SCN) is a rareE primary immunodeficiency disorder characterized by early onset recurrent infections in association with persistent severe agranulocytosis. To identify the clinical, immunohematological, and molecular characteristics of patients with SCN, 18 Iranian patients with the mean age of 8.8 +/- 5.8 years were investigated in this study. All of these patients experienced severe neutropenia; the mean of absolute neutrophil count was 281.4 +/- 137.7 cells/mm3. Bone marrow findings were typified by a myeloid maturation arrest at the promyelocyte-myelocyte stage in these patients. Molecular analysis revealed different mutations in the ELA-2 gene of one patient and in the HAX-1 gene of another three patients. The most common presenting complaints in these patients were superficial abscesses, oral ulcers, cutaneous infections, omphalitis, and pneumonia. During the course of illness, all patients developed mucocutaneous manifestations, and 16 cases had respiratory infections. The most commonly manifestations were abscesses, oral ulcers, pneumonia, periodontitis, otitis media, cutaneous infections, mucocutaneous candidiasis, and acute diarrhea. Three patients died because of a severe infection. Although SCN is a rare disorder, early onset of severe and recurrent infections should always raise a suspicion, which deserves further evaluation for detecting such disorder.
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ABSTRACT: Neutrophil elastase gene (ELANE) mutations are responsible for the majority of cases of severe congenital (CN) and cyclic neutropenia (CyN). We screened CN (n = 395) or CyN (n = 92) patients for ELANE mutations and investigated the impact of mutations on mRNA expression, protein expression and activity. We found 116 different mutations in 162 (41%) CN patients and 26 in 51 (55%) CyN patients, 69 of them were novel. CyN associated mutations were predicted to be more benign than CN associated mutations, but the mutation severity largely overlapped. The frequency of acquired CSF3R mutations, malignant transformation and the need for hematopoietic stem cell transplantation was significantly higher in CN patients with ELANE mutation than in ELANE mutation negative patients. Cellular elastase activity was reduced in neutrophils from CN/CyN patients, irrespective of the mutation status. In CN enzymatic activity was significantly lower in patients with ELANE mutations compared to those with wildtype ELANE. Despite differences in the spectrum of mutations in CN or CyN, type or localization of mutation only partially determine the clinical phenotype. Specific ELANE mutations have limited predictive value for leukemogenesis: the risk for leukemia was correlated with disease severity rather than with occurrence of an ELANE mutation.Human Mutation 06/2013; 34(6). DOI:10.1002/humu.22308 · 5.05 Impact Factor
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ABSTRACT: Many non-muscle cells assemble actin-myosin II structures such as stress fibers to produce force for motility and adhesion. Stress fibers also serve as mechanosensors that signal changes in cell organization and gene expression. Many components of non-muscle cell stress fibers are known, but key aspects of stress fiber organization and signaling mechanisms remain poorly understood. Our lab discovered that isoforms of the multifunctional elastic protein titin exist in non-muscle cells and are localized in stress fibers. In striated muscles, titin plays important roles as a structural protein that assembles and maintains the structure of the sarcomere as well as a mechanosensor that signals changes in protein turnover and gene expression. It is likely that that cellular titin (c-titin) plays similar structural and regulatory roles in non-muscle cells. C-titin, like striated muscle titin, contains a kinase domain near its C-terminus, which might play a role in titin signaling activity. Yeast two hybrid (Y2H) screening of a HeLa cell cDNA library revealed that the c-titin kinase domain interacts with the C-terminal end of Hax1. Hax1 is a ubiquitously expressed multifunctional protein that interacts with a variety of proteins including the actin regulating protein, cortactin. Hax1 plays a variety of roles in modulating apoptosis and in regulating the contribution of actin cytoskeleton to cell adhesion and motility. Additional Y2H analysis using alanine mutants revealed that a β-sheet cap region of the titin kinase domain interacts with a short highly conserved region of Hax1 encompassing residues 190-195 of the 279 residue protein. This titin kinase interaction region of Hax1 is near a possible phosphorylation site. Western blot analysis using a mouse monoclonal anti-serine/threonine primary antibody revealed that the titin kinase domain phosphorylates Hax1 in vitro. Immunolocalization revealed that some Hax1 and titin kinase domain colocalize in the lamellipodia of human mesenchymal stem cells. The interaction between the titin kinase domain and Hax1 points to a possible role for c-titin signaling in regulating actin cytoskeleton activity.
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ABSTRACT: Pediatric immunology came into sight in the second half of 20(th) century, when pediatricians and basic immunologists began to give attention to diagnosis and treatment of children with primary immunodeficiency diseases (PIDs). Understanding the genetic and mechanistic basis of PIDs provides unique insight into the functioning of the immune system. By progress in basic and clinical immunology, many infrastructural organizations and academic centers have been established in many countries worldwide to focus on training and research on the immune system and related disorders. Along with progress in basic and clinical immunology in the world, pediatric immunology had a good progress in Iran during the last 33-year period. Now, patients with PIDs can benefit from multidisciplinary comprehensive care, which is provided by clinical immunologists in collaboration with other specialists. Patients with history of recurrent and/or chronic infections suggestive of PIDs are evaluated by standard and research-based testing and receive appropriate treatment. The progress in PIDs can be described in three periods. Development of training program for clinical fellowship in allergy and immunology, multidisciplinary and international collaborative projects, primary immunodeficiency diseases textbooks, meetings on immunodeficiency disorders, improvement in diagnosis and treatment, and construction of Iranian primary immunodeficiency association, Students' research group for immunodeficiencies, Iranian primary immunodeficiency registry, and the immunological societies and centers were the main activities on PIDs during these years. In this article, we review the growth of modern pediatric immunology and PIDs status in Iran.Iranian Journal of Pediatrics 03/2010; 20(1):16-34. · 0.34 Impact Factor