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Turkish Journal of Haematology :... Nov 2020Wiskott-Aldrich syndrome (WAS) is an X-linked primary immune deficiency characterized by microthrombocytopenia, eczema, and recurrent infections. We aimed to evaluate...
OBJECTIVE
Wiskott-Aldrich syndrome (WAS) is an X-linked primary immune deficiency characterized by microthrombocytopenia, eczema, and recurrent infections. We aimed to evaluate the clinical features and outcomes of a WAS cohort.
MATERIALS AND METHODS
We retrospectively evaluated the clinical courses, immunological features, treatments, and outcomes in a total of 23 WAS patients together with data related to 11 transplanted cases among them between 1982 and 2019.
RESULTS
Before admission, 11 patients (48%) were misdiagnosed with immune thrombocytopenia. WAS scores were mostly 4 or 5. Eleven patients were transplanted and they had an overall survival rate of 100% during a median follow-up period of 8.5 years (range: 8 months to 20 years). Five patients who were not transplanted died at a median of 7 years (range: 2-26 years). Nontransplanted patients had high morbidity due to organ damage, mostly caused by autoimmunity, bleeding, and infections. Two novel mutations were also defined.
CONCLUSION
All male babies with microthrombocytopenia should be evaluated for WAS. Hematopoietic stem cell transplantation should be performed at the earliest age with the best possible donors.
Topics: Adolescent; Biomarkers; Child; Child, Preschool; Combined Modality Therapy; Diagnosis, Differential; Disease Management; Disease Susceptibility; Female; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulins, Intravenous; Infant; Infant, Newborn; Male; Patient Outcome Assessment; Phenotype; Prognosis; Reinfection; Symptom Assessment; Treatment Outcome; Wiskott-Aldrich Syndrome; Young Adult
PubMed: 32812413
DOI: 10.4274/tjh.galenos.2020.2020.0334 -
Frontiers in Immunology 2021Wiskott-Aldrich Syndrome, WAS/WAVE, is a rare, X-linked immune-deficiency disease caused by mutations in the gene, which together with its homolog, N-, regulates actin...
Wiskott-Aldrich Syndrome, WAS/WAVE, is a rare, X-linked immune-deficiency disease caused by mutations in the gene, which together with its homolog, N-, regulates actin cytoskeleton remodeling and cell motility. WAS patients suffer from microthrombocytopenia, characterized by a diminished number and size of platelets, though the underlying mechanism is not fully understood. Here, we identified FLI1 as a direct transcriptional regulator of and its binding partner . Depletion of either or in human erythroleukemic cells accelerated cell proliferation, suggesting tumor suppressor function of both genes in leukemia. Depletion of also led to a significant reduction in the percentage of CD41 and CD61 positive cells, which mark committed megakaryocytes. RNAseq analysis revealed common changes in megakaryocytic gene expression following FLI1 or WASP knockdown. However, in contrast to FLI1, WASP depletion did not alter expression of late-stage platelet-inducing genes. N-WASP was not regulated by FLI1, yet its silencing also reduced the percentage of CD41+ and CD61+ megakaryocytes. Moreover, combined knockdown of WASP and N-WASP further suppressed megakaryocyte differentiation, indicating a major cooperation of these related genes in controlling megakaryocytic cell fate. However, unlike WASP/WIP, N-WASP loss suppressed leukemic cell proliferation. WASP, WIP and N-WASP depletion led to induction of FLI1 expression, mediated by GATA1, and this may mitigate the severity of platelet deficiency in WAS patients. Together, these results uncover a crucial role for FLI1 in megakaryocyte differentiation, implicating this transcription factor in regulating microthrombocytopenia associated with Wiskott-Aldrich syndrome.
Topics: Animals; Base Sequence; Biomarkers; Cell Line; Chromatin Immunoprecipitation Sequencing; Cytoskeletal Proteins; Disease Models, Animal; Disease Susceptibility; Gene Expression Regulation; Humans; Intracellular Signaling Peptides and Proteins; Leukemia; Mice; Mice, Knockout; Promoter Regions, Genetic; Proto-Oncogene Protein c-fli-1; Signal Transduction; Thrombopoiesis; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein
PubMed: 33717090
DOI: 10.3389/fimmu.2021.607836 -
Immunobiology 2009Regulation of the actin cytoskeleton is crucial for many aspects of correct and cooperative functioning of immune cells, such as migration, antigen uptake and cell... (Review)
Review
Regulation of the actin cytoskeleton is crucial for many aspects of correct and cooperative functioning of immune cells, such as migration, antigen uptake and cell activation. The Wiskott-Aldrich Syndrome protein (WASp) is an important regulator of actin cytoskeletal rearrangements and lack of this protein results in impaired immune function. This review discusses recent new insights of the role of WASp at molecular and cellular level and evaluates how WASp deficiency affects important immunological features and how defective immune cell function contributes to compromised host defence.
Topics: Actins; Animals; Cell Movement; Dendritic Cells; Granulocytes; Humans; Immunological Synapses; Lymphocyte Activation; Lymphocytes; Macrophages; Monocytes; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein
PubMed: 19628299
DOI: 10.1016/j.imbio.2009.06.009 -
Frontiers in Immunology 2021Wiskott Aldrich syndrome (WAS) is characterized by bleeding manifestations, recurrent infections, eczema, autoimmunity, and malignancy. Over the last decade, improved...
BACKGROUND
Wiskott Aldrich syndrome (WAS) is characterized by bleeding manifestations, recurrent infections, eczema, autoimmunity, and malignancy. Over the last decade, improved awareness and better in-house diagnostic facilities at several centers in India has resulted in increased recognition of WAS. This study reports collated data across major primary immunodeficiency diseases (PID) centers in India that are involved in care of children with WAS and highlights the varied clinical presentations, genetic profile, and outcomes of patients in India.
METHODS
Request to share data was sent to multiple centers in India that are involved in care and management of patients with PID. Six centers provided requisite data that were compiled and analyzed.
RESULTS
In this multi-institutional cohort, clinical details of 108 patients who had a provisional diagnosis of WAS were received. Of these, 95 patients with 'definite WAS' were included Fourteen patients were classified as XLT and 81 patients as WAS. Median age at onset of symptoms of patients was 3 months (IQR 1.6, 6.0 months) and median age at diagnosis was 12 months (IQR 6,48 months). Clinical profile included bleeding episodes (92.6%), infections (84.2%), eczema (78.9%), various autoimmune manifestations (40%), and malignancy (2.1%). DNA analysis revealed 47 variants in 67 cases. Nonsense and missense variants were the most common (28.4% each), followed by small deletions (19.4%), and splice site defects (16.4%). We also report 24 novel variants, most of these being frameshift and nonsense mutations resulting in premature termination of protein synthesis. Prophylactic intravenous immunoglobulin (IVIg) was initiated in 52 patients (54.7%). Hematopoietic stem cell transplantation (HSCT) was carried out in 25 patients (26.3%). Of those transplanted, disease-free survival was seen in 15 patients (60%). Transplant related mortality was 36%. Outcome details were available for 89 patients. Of these, 37% had died till the time of this analysis. Median duration of follow-up was 36 months (range 2 weeks- 12 years; IQR 16.2 months- 70 months).
CONCLUSIONS
We report the first nationwide cohort of patients with WAS from India. Bleeding episodes and infections are common manifestations. Mortality continues to be high as curative therapy is not accessible to most of our patients.
Topics: Age Factors; Child, Preschool; Developing Countries; Disease-Free Survival; Female; Genetic Predisposition to Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulins, Intravenous; India; Infant; Male; Mutation; Phenotype; Risk Assessment; Risk Factors; Time Factors; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein
PubMed: 33936041
DOI: 10.3389/fimmu.2021.627651 -
Archives of Disease in Childhood Dec 1967
Topics: Blood Cell Count; Eczema; Humans; Infant, Newborn; Isoantibodies; Male; Melena; Pedigree; Sex Factors; Wiskott-Aldrich Syndrome
PubMed: 6073827
DOI: 10.1136/adc.42.226.604 -
The Israel Medical Association Journal... May 2002
Review
Topics: Humans; Proteins; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein
PubMed: 12040832
DOI: No ID Found -
The Journal of Allergy and Clinical... Mar 2019
Topics: Child; Child, Preschool; Hematopoietic Stem Cell Transplantation; Hemorrhage; Humans; Infant; Platelet Count; Splenectomy; Wiskott-Aldrich Syndrome
PubMed: 30048768
DOI: 10.1016/j.jaip.2018.07.009 -
Revista Chilena de Pediatria Feb 2020Guillain-Barre Syndrome (GBS) is rarely diagnosed in the first year of life. The association of GBS with Wiskott-Aldrich syndrome (WAS) is even less frequent and has...
INTRODUCTION
Guillain-Barre Syndrome (GBS) is rarely diagnosed in the first year of life. The association of GBS with Wiskott-Aldrich syndrome (WAS) is even less frequent and has been previously reported in only two children to our knowledge. Hydrocephalus is a known but rare complication of GBS.
OBJECTIVE
To describe the case of an infant in which GBS, WAS and hydrocephalus appear clinically associated.
CLINICAL CASE
A nine-months-old male infant with a history of WAS was admitted to our ICU with acute hypotonia and poor general condition. He developed flaccid paralysis, absent deep tendon reflexes, and respiratory failure. A lumbar puncture showed albuminocytologic dissociation. GBS was suspected and an electromyography was performed, showing a demyelinating polyneuropathy. He was successfully treated with intravenous immunoglobulins. During hospitalization, he presented intermittent bradycardia, so a brain CT scan was performed, showing acute hydrocephalus which was managed through an external ventricular drain achieving favorable response. In the long term, the patient underwent bone marrow transplant and had to be reoperated due to valve-related complications. However, his psychomotor development is normal, with no obvious neurological sequelae.
CONCLUSION
We present the third case of GBS in a patient with WAS, which is the first infant younger than one year. Additionally, he presented acute hydrocephalus as a complication of GBS. We suggest considering these three comorbidities since their early diagnosis and prompt management allow bet ter neurological recovery and avoid potentially lethal complications.
Topics: Guillain-Barre Syndrome; Humans; Hydrocephalus; Infant; Male; Wiskott-Aldrich Syndrome
PubMed: 32730420
DOI: 10.32641/rchped.v91i1.1208 -
Orphanet Journal of Rare Diseases Dec 2022Wiskott-Aldrich syndrome (WAS) is a rare X-linked immunodeficiency disorder caused by abnormal expression of the WAS protein (WASp) due to mutations in the WAS gene, and...
BACKGROUND
Wiskott-Aldrich syndrome (WAS) is a rare X-linked immunodeficiency disorder caused by abnormal expression of the WAS protein (WASp) due to mutations in the WAS gene, and is generally characterized by microthrombocytopenia, eczema, recurrent infections, and high susceptibility to autoimmune complications and hematological malignancies.
RESULTS
Herein, we identified a novel WAS mutation (c.158 T > C) using next-generation sequencing in a Chinese pedigree with WAS. The expression of WASp in the patients and their families was detected by flow cytometry and western blot analysis. To explore the exon-splicing effect of intron mutations and the correlation between the genotype and clinical phenotype, four groups of wild-type (WT), exon mutant, intron mutant, and combined mutant recombinant plasmids were transfected into COS-7 cells in vitro. The proband showed dramatically decreased WASp expression, while the female carriers showed a slightly lower level of WASp. The expression of products in the mutant and WT recombinant plasmids was detected by real-time fluorescence quantitative polymerase chain reaction (PCR), which showed a significant reduction in the combined mutant group than in the WT, exon mutant, and intron mutant groups. The length of the expression products in the four groups showed no differences, each containing 360 base pairs. Sequence analysis confirmed that the c.158 T > C mutation appeared in the exon mutant and combined mutant groups, whereas the intron variant c.273 + 14C > T caused no other sequence changes.
CONCLUSION
This study confirmed that the intron mutation did not affect the splicing of exons and excluded the influence of the double mutations at the transcription level on the severe clinical manifestations in the cousin. This in vitro study provided new insights into the pathogenesis of intronic mutations in WAS.
Topics: Humans; Female; Wiskott-Aldrich Syndrome; Pedigree; East Asian People; Mutation; RNA Splicing
PubMed: 36550574
DOI: 10.1186/s13023-022-02589-y -
Frontiers in Immunology 2023The abnormal expression of the Wiskott-Aldrich syndrome protein (WASP) encoded by the Wiskott-Aldrich syndrome (WAS) gene has been implicated in tumor invasion and...
INTRODUCTION
The abnormal expression of the Wiskott-Aldrich syndrome protein (WASP) encoded by the Wiskott-Aldrich syndrome (WAS) gene has been implicated in tumor invasion and immune regulation. However, prognostic implications of WAS and its correlation tumor infiltrating in renal clear cell carcinoma (ccRCC) is not clear cut.
METHODS
The correlation between WAS expression, clinicopathological variables and clinical outcomes were evaluated using The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), Tumor Immune Estimation Resource (TIMER), UALCAN, Gene Expression Profiling Interaction Analysis (GEPIA), Kaplan-Meier (KM) plotter and other databases. Furthermore, we assessed the transcription expression of WAS in renal cancer tissues, various renal carcinoma cell lines and human renal tubular cells (HK2) using quantitative polymerase chain reaction (qPCR). A comprehensive analysis of multiple databases including TIMER, GEPIA, TISIDB, ESTIMATE algorithm, and CIBERSORT algorithm were performed to determine the correlation between WAS and tumor infiltrating immune cells in ccRCC.
RESULTS
The results displayed an increase in WAS mRNA level in ccRCC compared to normal tissue. WAS protein level was found highly expressed in cancer tissues, particularly within renal tumor cells via the human protein atlas (HPA). Interestingly, we found that elevated WAS expression was significantly positively correlated with the infiltration of CD8+ T cells, B cells, Monocytes, Neutrophils, Macrophages, T cell regulation, NK cells, and Dendritic cells in ccRCC. Bioinformatics demonstrated a strong correlation between WAS expression and 42 immune checkpoints, including the T cell exhaustion gene PD-1, which is critical for exploring immunotherapy for ccRCC. We revealed that patients with high WAS expression were less sensitive to immunotherapy medications.
CONCLUSION
In conclusion, our study identified that WAS was a prognostic biomarker and correlated with immune infiltrates in ccRCC.
Topics: Humans; Carcinoma, Renal Cell; Prognosis; Wiskott-Aldrich Syndrome; Carcinoma; Kidney Neoplasms; Biomarkers
PubMed: 37122750
DOI: 10.3389/fimmu.2023.1102824