https://www.cell.com/cell/pdf/0092-8674(94)90528-2.pdf

Isolation of a novel gene mutated in Wiskott-Aldrich syndrome

Wiskott–Aldrich Syndrome Protein, a Novel Effector for the GTPase CDC42Hs, Is Implicated in Actin Polymerization

Here we identify a 65 kDa protein (N-WASP) from brain that binds the SH3 domains of Ash/Grb2 The sequence is homologous to Wiskott-Aldrich syndrome protein (WASP) N-WASP has several functional motifs, such as a pleckstrin homology (PH) domain and cofilin-homologous region, through which N-WASP depolymerizes actin filaments When overexpressed in COS 7 cells, the wild-type N-WASP causes several surface protrusions where N-WASP co-localizes with actin filaments Epidermal growth factor (EGF) treatment induces the complex formation of EGF receptors and N-WASP, and produces microspikes On the other hand, two mutants, C38W (a point mutation in the PH domain) and deltaVCA (deletion of the actin binding domain), localize predominantly in the nucleus and do not cause a change in the cytoskeleton, irrespective of EGF treatment Interestingly, the C38W PH domain binds less effectively to phosphatidylinositol 4,5-bisphosphate (PIP2) than the wild-type PH domain These results suggest the importance of the PIP2 binding ability of the PH domain and the actin binding for retention in membranes Collectively, we conclude that N-WASP transmits signals from tyrosine kinases to cause a polarized rearrangement of cortical actin filaments dependent on PIP2

N-WASP, a novel actin-depolymerizing protein, regulates the cortical cytoskeletal rearrangement in a PIP2-dependent manner downstream of tyrosine kinases.

TABLE OF CONTENTS I. Preface S1 II. Executive Summary S2 III. Algorithms S7 IV. Summary Statements S14 V. General Considerations S20 VI. Humoral Immunodeficiencies S24 VII. Cellular Immunodeficiencies S30 VIII. Combined Immunodeficiencies S33 IX. Phagocytic Cell Disorders S40 X. Complement Deficiencies S43 XI. Acknowledgments S45 XII. References S45 XIII. Appendix S61

/pdf/practice-parameter-for-the-diagnosis-and-management-of-51jodutzi0.pdf

Practice parameter for the diagnosis and management of primary immunodeficiency.

https://www.cell.com/immunity/pdf/S1074-7613(00)80590-7.pdf

Wiskott-Aldrich Syndrome Protein-Deficient Mice Reveal a Role for WASP in T but Not B Cell Activation

The Wiskott-Aldrich syndrome (WAS) is an X-chromosome-linked recessive disease characterized by eczema, thrombocytopenia, and immunodeficiency. The disease gene has been localized to the proximal short arm of the X chromosome and recently isolated through positional cloning. The function of the encoded protein remains undetermined. In this study we have characterized mutations in 12 unrelated patients to confirm the identity of the disease gene. We have also revised the coding sequence and genomic structure for the WAS gene. To analyze further the transmittance of the disease gene, we have characterized a polymorphic microsatellite at the DXS6940 locus within 30 kb of the gene and demonstrate the inheritance of the affected alleles in families with a history of WAS.

https://www.pnas.org/content/pnas/92/10/4706.full.pdf

Identification of mutations in the Wiskott-Aldrich syndrome gene and characterization of a polymorphic dinucleotide repeat at DXS6940, adjacent to the disease gene.

The defective gene responsible for the recessively inherited immunodeficiency X-linked agammaglobulinemia (XLA) has been shown to encode a cytoplasmic protein tyrosine kinase of the Src family designated Btk (Bruton's tyrosine kinase). To facilitate the search for germline mutations of the Btk gene, we have characterized its genomic structure. Eighteen introns were positioned within the approximately 37 kb gene. Each of the exon/intron boundaries were defined and sequenced, and all but two conform to consensus sequences. We have utilized the genomic organization of Btk and the intervening sequence data to design an assay for amplifying each of the 19 exons from XLA patient DNA for single strand conformation polymorphism (SSCP) analysis. By using this method we have identified mutations in 12 of 14 unrelated affected males: seven different base substitutions and two small deletions. Two of the mutations described in exon 15 of the kinase domain were found in more than one patient and may represent a mutation hot spot. Exon scanning has proven to be a valuable method for identifying the patient mutations in genomic DNA without the use of cDNA. The mutations are easily confirmed with direct sequencing of the amplified exons. This approach will greatly benefit XLA family studies involving carrier detection and prenatal diagnosis. In addition, the mutations identified may reveal residues involved in the specific protein interactions necessary in the B-cell developmental pathway, of which Btk is an integral component.

Genomic organization of the Btk gene and exon scanning for mutations in patients with X-linked agammaglobulinemia

The Wiskott-Aldrich syndrome (WAS) arises from defects of the X-chromosome gene WASP. Severe platelet defects, thrombocytopenia with small platelets, are a hallmark of the disease, but clinical immunodeficiency based in lymphocyte dysfunction varies from negligible to life threatening among WAS patients. To address the connection between WASP mutations and clinical outcomes, we generated and characterized a panel of patient B cell lines. Three cell lines from patients with exon 2 missense mutations and mild immune dysfunction were found to express substantial levels of WASP mRNA and protein. On the other hand, 8 of 10 cell lines from patients with moderate or severe immune dysfunction lack detectable WASP protein. The findings suggest that the clinical variability of the WAS can partially be explained by the level of WASP protein in the patient's cells.

Variable expression of WASP in B cell lines of Wiskott-Aldrich syndrome patients.

Scanning of the Wiskott-Aldrich syndrome (WAS) gene: identification of 18 novel alterations including a possible mutation hotspot at Arg86 resulting in thrombocytopenia, a mild WAS phenotype

The identification and characterization of two promoters and the complete genomic sequence for the Wiskott-Aldrich syndrome gene.

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