ISOLATION OF A NOVEL GENE MUTATED IN WISKOTT-ALDRICH SYNDROME

PEDIATRICS ◽  
1995 ◽  
Vol 96 (2) ◽  
pp. 411-411
Author(s):  
Sanober Meer ◽  
Andrew Liu
Keyword(s):  
Genetic Locus ◽  
Close Correlation ◽  
Gene Replacement ◽  
Specific Gene ◽  
Severe Thrombocytopenia ◽  
Wiskott Aldrich Syndrome ◽  
Cdna Sequences ◽  
Novel Gene ◽  
Increased Risk ◽  
Was Gene

Purpose of the Study. Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disorder associated with severe thrombocytopenia, eczema, bloody diarrhea, B & T cell immunodeficiency and increased risk of malignancies. This study describes the isolation of a novel gene, WAS Protein (WASP) which is mutated in four WAS patients. Methods. The WAS gene had been localized previously by linkage analyses to a >1 Megabase region in chromosome Xp11.22-p11.23. To isolate the WAS gene, a clone contig was constructed in this interval, followed by isolation of cDNA sequences. Results. A novel gene, WASP, was isolated, which is believed to be the main genetic locus in WAS. This is supported by the following findings. First, the gene was isolated from the chromosome Xp11.22-p11.23 interval previously identified as containing the WAS gene. Second, lymphoblasts from two unrelated patients clinically diagnosed with WAS failed to express WASP on Northern blots. Two additional WAS patients were also found to have point substitution mutations of an arginine residue. Finally, WASP is expressed in lymphocytic and megakaryocytic cell lineages, indicating a close correlation between tissue-specific gene expression and the disease manifestations of WAS. Reviewer's Comments. This paper succinctly describes a major breakthrough in the identification of the defective gene in WAS, which is found to be mutated in the four WAS patients studied. This finding brings direction and impetus to research on WAS, provides improved methods for detecting WAS, and brings the possibility of gene replacement therapy for WAS much closer.

Molecular Analysis of WASP Gene - First Report from India.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3217-3217
Author(s):  
Rintu Rebecca Jacob ◽  
Reena Rajasekar ◽  
Eunice S. Edison ◽  
Biju George ◽  
Vikram Mathews ◽  
...  
Keyword(s):  
Functional Significance ◽  
Molecular Basis ◽  
Direct Sequencing ◽  
Mutation Screening ◽  
Clinical Severity ◽  
Severe Thrombocytopenia ◽  
Molecular Defects ◽  
Splice Site Prediction ◽  
Increased Risk ◽  
Was Gene

Abstract Wiskott Aldrich Syndrome (WAS) is an X-linked recessive disorder associated with severe thrombocytopenia, eczema, bloody diarrhea, profound immunodeficiency and an increased risk of malignancies. More than 200 mutations have been described in the gene encoding the WAS protein (WASP). We report here the molecular basis of WAS in six patients from India. Diagnosis of WAS/X- linked thrombocytopenia (XLT) was based on low platelet count (9000– 1, 25,000/mm3), presence of small platelets (mean: 6.2fl) and detection of WASP by flowcytometry. Patients evaluated in the study could be classified as classical WAS (n=3) and XLT (n=3) depending on the clinical severity of their disease (Zhu et.al 1995). All 12 exons and flanking splice-sites of WAS gene were amplified by polymerase chain reaction (PCR) using primers and PCR conditions adopted with modifications from Kwan et al (PNAS1995;92:4706). Mutation analysis was accomplished by conformation sensitive gel electrophoresis (CSGE) and direct sequencing. Abnormal banding pattern was observed only in 4 patients after CSGE analysis. c.995 C>T could not be detected by CSGE but was detected by direct sequencing. The types of molecular defects identified in five patients were as follows: nonsense - 2, deletion - 1 and duplication - 1. Three of these alterations (see table) have been reported previously and are associated with classical WAS. In patients detected to have nonsense mutations, flowcytometric analysis of WASP exhibited high values (table) not consistent with reported western blotting data in these mutations. c.307+10-11dupC was observed in two patients (brothers) with thrombocytopenia, small platelets and mild bleeding. This duplication is not a reported polymorphism. Though this duplication changes the acceptor splice site prediction score from 0.83 to 0.91, its functional significance has not been determined and requires further evaluation. The sixth patient in our study had thrombocytopenia (15,000–45,000/mm3), small platelets (4.8–7.2 fl), mild bleeding, similar family history and normal expression of WASP (86.2%). No mutation has been identified in the coding region of WAS gene in this patient either by CSGE or direct sequencing. Our data shows that the molecular basis for WAS is heterogenous in India. This is the first study evaluating mutations in WAS gene from India. Further mutation screening of patients with WAS will allow the genetic definition, phenotype-genotype corelation, carrier detection and prenatal diagnosis of this condition. Molecular defects observed in WAS patients Patient ID Flow cytometry (%) Mutation *-Reported mutation, ♦-Functional Significance not known PD-22 WASP D1-98.5, WASPB9 - 94.8 c.665C>T, p.Arg211X* PD-16 WASP B9- 6.7 c. 1035-1036 delG, p.Gly314ValfsX120* PD-21 WASP D1-97.2, WASP B9-91.2 c.995 C>T, p. Arg321X* PD-34, PD-35 (siblings) WASP D1-3.6, WASP B9-2; D1-1.8, B9-1 c.307+10-11 dupC♦ PD-28 WASP D1 - 86.2 Mutation not detected

scholarly journals Development of flow cytometry assay for Wiskott–Aldrich syndrome diagnosis by WASP protein evaluation

2020 ◽  
Vol 19 (2) ◽  
pp. 141-151
Author(s):  
D. E. Pershin ◽  
O. B. Lodoeva ◽  
M. S. Fadeeva ◽  
I. V. Mersiyanova ◽  
A. L. Khoreva ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Threshold Value ◽  
Clinical Severity ◽  
Malignant Neoplasms ◽  
Flow Cytometry Assay ◽  
Old Patients ◽  
Wiskott Aldrich Syndrome ◽  
Increased Risk ◽  
Short Period ◽  
Was Gene

Wiskott–Aldrich syndrome (WAS) is a rare X-linked primary immunodeficiency characterized by microplatelet thrombocytopenia, eczema, frequent infections and an increased risk of autoimmune disorders and malignant neoplasms. Mutation detection in WAS gene is the gold standard for diagnosis of this disorder. This gene encodes a WASP protein, which works as regulator of cell cytoskeleton and is involved in the transmission of many intracellular signals. Nowadays there is no rapid and reliable method that allows to confirm WAS in a short period of time. Early detection of WAS in patients enables initiation of a donor search and preparation for the HSCT procedure. It also helps to avoid the development of severe and life-threatening conditions during waiting for genetic confirmation of the diagnosis by using pathogenetic therapy. Currently flow cytometry is one of the leading laboratory methods that permits to get the information about the expression of a protein in several hours. The study below describes rapid and reliable based on flow cytometry assay for WAS diagnosis. The study was approved by the Independent Ethics Committee and the Scientific Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology, and Immunology. The study included 46 patients with suspected WAS from 2 months to 17 years old. Patients were examined from January 2018 to January 2020. WAS gene defect was confirmed in 35 patients. It was calculated that normal threshold value for WASP expression is 7.07 with sensitivity and specificity 100% and 93.1% respectively. Besides negative correlation between WASP expression index and WAS clinical severity was shown (r = –0.63). This flow cytometry assay can be used for chimerism detection in WAS patients after HSCT. The flow cytometry assay for WASP protein evaluation is rapid, highly sensitive and highly specific. It allows to speed up diagnosis of this disorder.

scholarly journals Vitamin D and Cardiovascular Disease: An Updated Narrative Review

2021 ◽  
Vol 22 (6) ◽  
pp. 2896
Author(s):  
Armin Zittermann ◽  
Christian Trummer ◽  
Verena Theiler-Schwetz ◽  
Elisabeth Lerchbaum ◽  
Winfried März ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Vitamin D ◽  
High Risk ◽  
General Population ◽  
Vitamin D Deficiency ◽  
Specific Gene ◽  
Vitamin D Status ◽  
Cvd Risk ◽  
Severe Vitamin ◽  
Increased Risk

During the last two decades, the potential impact of vitamin D on the risk of cardiovascular disease (CVD) has been rigorously studied. Data regarding the effect of vitamin D on CVD risk are puzzling: observational data indicate an inverse nonlinear association between vitamin D status and CVD events, with the highest CVD risk at severe vitamin D deficiency; however, preclinical data and randomized controlled trials (RCTs) show several beneficial effects of vitamin D on the surrogate parameters of vascular and cardiac function. By contrast, Mendelian randomization studies and large RCTs in the general population and in patients with chronic kidney disease, a high-risk group for CVD events, largely report no significant beneficial effect of vitamin D treatment on CVD events. In patients with rickets and osteomalacia, cardiovascular complications are infrequently reported, except for an increased risk of heart failure. In conclusion, there is no strong evidence for beneficial vitamin D effects on CVD risk, either in the general population or in high-risk groups. Whether some subgroups such as individuals with severe vitamin D deficiency or a combination of low vitamin D status with specific gene variants and/or certain nutrition/lifestyle factors would benefit from vitamin D (metabolite) administration, remains to be studied.

A novel mutation of the WAS gene in a patient with Wiskott-Aldrich syndrome presenting with recalcitrant viral warts

2010 ◽  
Vol 60 (2) ◽  
pp. 120-122 ◽  
Author(s):  
Jin Ki Kim ◽  
Moon Soo Yoon ◽  
Ji Young Huh ◽  
Hee-Jin Kim ◽  
Dong Hyun Kim
Keyword(s):  
Novel Mutation ◽  
Wiskott Aldrich Syndrome ◽  
Was Gene

Abstract 16543: Severe Thrombocytopenia is Common in Adults Undergoing Venoarterial Extracorporeal Membrane Oxygenation and is Predictive of Hemorrhage

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Tia C Kohs ◽  
Vikram Raghunathan ◽  
Patricia Liu ◽  
Ramin Amirsoltani ◽  
Michael Oakes ◽  
...  
Keyword(s):  
Overall Survival ◽  
Logistic Regression ◽  
Platelet Count ◽  
Extracorporeal Membrane Oxygenation ◽  
Clinical Implications ◽  
Severe Thrombocytopenia ◽  
Multivariate Logistic Regression ◽  
Membrane Oxygenation ◽  
Increased Risk ◽  
Va Ecmo

Introduction: Extracorporeal membrane oxygenation (ECMO) is used to provide circulatory support and facilitate gas exchange via cardiopulmonary bypass. The relationship between ECMO and the incidence of severe thrombocytopenia (platelet count <50 x 10 9 /L) and subsequent clinical consequences are ill defined. We aimed to identify the risk factors for the development of thrombocytopenia and its clinical implications. Methods: This is a single-center retrospective cohort study of adults who received venoarterial (VA) ECMO. We examined consecutive platelet counts while on ECMO. Univariate logistic regression was used to determine if mean platelet count, platelet count range, or severe thrombocytopenia were predictors of overall survival, hemorrhage and thrombosis. A multivariate logistic regression model was used to identify factors that contribute to the development of the aforementioned patient outcomes. Results: In our cohort, 33 patients were included with a mean age of 55 years and duration of ECMO of 5.9 days. All patients received heparin, 33.3% received antiplatelet therapy and 45.5% developed severe thrombocytopenia. In univariate, analysis the development of severe thrombocytopenia increased the odds of major bleeding by 450% (OR 5.500, 95% CI 1.219 - 24.813, P -value 0.027), and the odds of surviving hospitalization decreased 84.1% (OR 0.159, 95% CI 0.033 - 0.773, P -value 0.023). Multivariate logistic regression controlling for additional clinical variables found no significant association between the development of severe thrombocytopenia and rates of thrombosis, hemorrhage, or overall survival. Platelet count decreased over time while on ECMO. Conclusions: Nearly half of the patients requiring VA-ECMO developed severe thrombocytopenia, which was associated with an increased risk of hemorrhage and in-hospital mortality. Additional studies are required to clarify the clinical implications of severe thrombocytopenia in ECMO patients.

Heparin-induced thrombocytopenia: when a low platelet count is a mandate for anticoagulation

Hematology ◽  
2009 ◽  
Vol 2009 (1) ◽  
pp. 225-232 ◽  
Author(s):  
Thomas L. Ortel
Keyword(s):  
Platelet Count ◽  
Heparin Therapy ◽  
Severe Thrombocytopenia ◽  
Drug Induced ◽  
Platelet Factor ◽  
Heparin Induced Thrombocytopenia ◽  
Immune Mediated ◽  
Number Of Patients ◽  
Increased Risk ◽  
Antibody Levels

Abstract Heparin-induced thrombocytopenia (HIT) is an immune-mediated disorder caused by the development of antibodies to platelet factor 4 (PF4) and heparin. The thrombocytopenia is typically moderate, with a median platelet count nadir of ~50 to 60 × 109 platelets/L. Severe thrombocytopenia has been described in patients with HIT, and in these patients antibody levels are high and severe clinical outcomes have been reported (eg, disseminated intravascular coagulation with microvascular thrombosis). The timing of the thrombocytopenia in relation to the initiation of heparin therapy is critically important, with the platelet count beginning to drop within 5 to 10 days of starting heparin. A more rapid drop in the platelet count can occur in patients who have been recently exposed to heparin (within the preceding 3 months), due to preformed anti-heparin/PF4 antibodies. A delayed form of HIT has also been described that develops within days or weeks after the heparin has been discontinued. In contrast to other drug-induced thrombocytopenias, HIT is characterized by an increased risk for thromboembolic complications, primarily venous thromboembolism. Heparin and all heparin-containing products should be discontinued and an alternative, non-heparin anticoagulant initiated. Alternative agents that have been used effectively in patients with HIT include lepirudin, argatroban, bivalirudin, and danaparoid, although the last agent is not available in North America. Fondaparinux has been used in a small number of patients with HIT and generally appears to be safe. Warfarin therapy should not be initiated until the platelet count has recovered and the patient is systemically anticoagulated, and vitamin K should be administered to patients receiving warfarin at the time of diagnosis of HIT.

scholarly journals Gene therapy for Wiskott-Aldrich Syndrome—Long-term reconstitution and clinical benefits, but increased risk for leukemogenesis

Rare Diseases ◽  
2014 ◽  
Vol 2 (1) ◽  
pp. e947749 ◽  
Author(s):  
Christian Joerg Braun ◽  
Maximilian Witzel ◽  
Anna Paruzynski ◽  
Kaan Boztug ◽  
Christof von Kalle ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Wiskott Aldrich Syndrome ◽  
Increased Risk ◽  
Clinical Benefits

scholarly journals A shared susceptibility locus in p53 for both gastric cancer and esophageal cancer in a northwestern Chinese population

2019 ◽  
Author(s):  
Juan Cao ◽  
Zhiqiang Chen ◽  
Jing Chen ◽  
Yanjie You ◽  
Chaoyong Tian ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Esophageal Cancer ◽  
Genetic Variants ◽  
Genetic Locus ◽  
Immunohistochemical Method ◽  
Regression Analyses ◽  
Gastrointestinal Cancers ◽  
P53 Expression ◽  
Increased Risk ◽  
Upper Gastrointestinal

Abstract Background Upper gastrointestinal cancers are the leading causes of cancer-related deaths in Northwest China and share many similarities in terms of histological type, risk factors and genetic variants. We hypothesized that shared common genetic SNPs among eight SNPs in the p53 pathway existed among Ningxia gastric cancer (GC) and esophageal cancer (EC) patients. Methods A total of 180 GC cases, 113 EC cases and 358 cancer-free control subjects from a high-incidence area for upper gastrointestinal cancers in Ningxia, China, were enrolled in this study. The genotyping of 8 SNPs was performed using PCR direct sequencing. P53 expression in GC and EC tissues was examined using the S-P immunohistochemical method. Multiple logistic regression analyses were used to estimate the association between genotypes and GC or EC risks. Kaplan-Meier and multivariate Cox regression analyses were carried out to evaluate the associations between genetic variants and overall survival. Result rs1042522 was a common genetic locus shared by both Ningxia GC and EC patients. Compared with the rs1042522 Pro allele, the rs1042522 Arg allele increased the GC risk by 1.810 times and the EC risk by 2.285 times. Additionally, patients who carried the rs1042522 Arg allele and who also smoked or consumed alcohol had an increased risk for GC and EC. Cox survival analysis showed that neither p53 nor rs1042522 had an effect on the prognosis of GC and EC patients. Conclusion rs1042522 was a common genetic locus responsible for susceptibility shared by both northwestern GC and EC Chinese patients. Tobacco smoking and alcohol drinking further enhanced the cancer risk in our study.

scholarly journals Current State of Preeclampsia Mouse Models: Approaches, Relevance, and Standardization

2021 ◽  
Vol 12 ◽  
Author(s):  
Christopher A. Waker ◽  
Melissa R. Kaufman ◽  
Thomas L. Brown
Keyword(s):  
Mouse Models ◽  
Molecular Mechanisms ◽  
Human Condition ◽  
Definitive Treatment ◽  
Specific Gene ◽  
Adenoviral Infection ◽  
Physiological Relevance ◽  
Increased Risk ◽  
Therapeutic Development ◽  
Surgical Manipulation

Preeclampsia (PE) is a multisystemic, pregnancy-specific disorder and a leading cause of maternal and fetal death. PE is also associated with an increased risk for chronic morbidities later in life for mother and offspring. Abnormal placentation or placental function has been well-established as central to the genesis of PE; yet much remains to be determined about the factors involved in the development of this condition. Despite decades of investigation and many clinical trials, the only definitive treatment is parturition. To better understand the condition and identify potential targets preclinically, many approaches to simulate PE in mice have been developed and include mixed mouse strain crosses, genetic overexpression and knockout, exogenous agent administration, surgical manipulation, systemic adenoviral infection, and trophoblast-specific gene transfer. These models have been useful to investigate how biological perturbations identified in human PE are involved in the generation of PE-like symptoms and have improved the understanding of the molecular mechanisms underpinning the human condition. However, these approaches were characterized by a wide variety of physiological endpoints, which can make it difficult to compare effects across models and many of these approaches have aspects that lack physiological relevance to this human disorder and may interfere with therapeutic development. This report provides a comprehensive review of mouse models that exhibit PE-like symptoms and a proposed standardization of physiological characteristics for analysis in murine models of PE.

Sign in / Sign up

Export Citation Format

Share Document