Wiskott Aldrich syndrome caused by a novel mutation in WASP gene presenting with a mild phenotype

Background: Wiskott–Aldrich syndrome (WAS) is X-linked recessive disorder associated with combined immunodeficiency, microthrombocytopenia, eczema, and an increased risk of autoimmunity and cancer. Aim: To report the clinical presentation, immune features, and genetic mutation in a patient with a novel mutation in the WASP gene causing a mild phenotype of Wiskott Aldrich syndrome Methods: Patient’s chart was reviewed. We report the phenotypical and laboratory characteristics of a patient with a mild phenotype of Wiskott Aldrich syndrome with a novel mutation found by WASP gene sequence analysis. Results: This patient presented with thrombocytopenia and 3 episodes of otitis media at 24 months of age, with no other significant manifestations suggestive of immunodeficiency or immune dysregulation. A missense mutation was found in exon 12 of WASP gene, C1498>T, leading to a Trp500Arg amino acid change. Currently he is 15 years old and remained in good health, free of infections or other complication to date. Conclusion: Genetic analysis is helpful for the diagnosis of WAS patients; our patient’s mutation was found to cause a mild phenotype of WAS. Statement of Novelty: We describe a patient with a mild phenotype of WAS with a novel mutation in the WASP gene, thus, expanding the spectrum of WASP gene mutations.

Mutational screening of WASP gene in patients with Wiskott-Aldrich syndrome

The Wiskott-Aldrich syndrome (WAS) is a rare X-linked recessive immunodeficiency disorder characterized by thrombocytopenia and small-sized platelets, eczema, recurrent bacterial and viral infections, higher incidence of autoimmunity and an increased risk of malignancies. WAS occurs due to the mutation or loss of Wiskott-Aldrich Syndrome Protein (WASP) gene located on Xp11.22 – p11.23 of the short arm of the X chromosome. The absence of functional WASP leads to severe clinical symptoms that results in the deaths of patients if they are not diagnosed and treated early. The objective of the study was to identify mutations in the WASP gene of families with children diagnosed with WAS.The whole coding sequence and the intron-exon flanking regions of the WASP were sequenced by Sanger method. Two cases of children who has WAS were found tocarrymutations in the WASP gene. A c.702insAC mutation leadeda frameshift at position of codon 236 and terminated the protein at the position of codon 262 was identified in patient WA007 and a c.91G>A mutation that transformed glutamic acid to lysineat codon 31 was determined in patient WA010.This study provides a data set and screening of mutations in theWASP gene inVietnamese patientsto further identify the genetic causes and contribute to the clinical management and genetic counseling for the affected families.

Wiskott–Aldrich syndrome that was initially diagnosed as immune thrombocytopenic purpura secondary to a cytomegalovirus infection

Wiskott–Aldrich syndrome is a rare X-linked recessive disease resulting from variations in the WAS gene. Wiskott–Aldrich syndrome is sometimes difficult to differentiate from immune thrombocytopenic purpura. A 2-month-old boy was admitted to our hospital for purpura and thrombocytopenia. His mean platelet volume was reported to be normal. Treatment with intravenous immunoglobulins failed to improve the patient’s platelet count. Subsequently, an acute cytomegalovirus infection was confirmed by serological testing and antigenemia. The patient was diagnosed with immune thrombocytopenic purpura secondary to a cytomegalovirus infection. However, based on the patient’s clinical course and the refractoriness of his condition, Wiskott–Aldrich syndrome was strongly suspected. Through direct sequencing of the genomic DNA of the Wiskott–Aldrich syndrome protein (WASP) gene, we identified a novel missense mutation in exon 3 of the patient’s WASP gene (c. 343 C>T, p. H115T), and the patient was diagnosed with Wiskott–Aldrich syndrome at 3 months after onset. Children with Wiskott–Aldrich syndrome are often initially diagnosed with immune thrombocytopenic purpura, which can lead to inappropriate treatment and delays to life-saving definitive therapy. Our findings imply that Wiskott–Aldrich syndrome should be considered as a differential diagnosis in cases of refractory immune thrombocytopenic purpura combined with a cytomegalovirus infection.

Wiskott-Aldrich Syndrome Protein (WASP) Is An Effector of Kit Signaling.

Wiskott-Aldrich Syndrome (WAS) is an X-linked recessive immunodeficiency disorder with eczema, thrombocytopenia and high susceptibility to opportunistic and pyogenic infections. The gene product of the WAS locus, WAS protein (WASP), is expressed in a hematopoietic-specific fashion and regulates cytoskeletal actin reorganization via Cdc42 and Arp2/3 interactions. Non-random inactivation of the X chromosome carrying the defective WASP gene in all peripheral blood cells from obligate female carriers of WAS suggests a selective advantage of hematopoietic stem cells or immature progenitor cells expressing the intact WASP gene. Because such progenitor cells are dependent on the Kit receptor/Kit ligand (KL) pathway, we tested whether or not WASP plays a role in signaling responses through Kit. WASP and interacting proteins WIP and Arp2/3 were strongly phosphorylated in response to KL stimulation of Mo7e cells. Time kinetics revealed onset of tyrosine phosphorylation of WASP as early as 1 min and a maximum at 5 min after KL stimulation. Although real-time KL-induced actin reorganization and KL-mediated spreading of bone marrow-derived mast cells (BMMC) on fibronectin-coated surfaces were grossly normal, KL-induced formation of filopodia was significantly decreased in number and size in the absence of WASP. In addition, KL-induced calcium-flux in BMMCs was aberrant in the absence of WASP suggesting that KL-dependent calcium signals and cytoskeletal rearrangement are linked through WASP. When BMMC cultures were established from WASP heterozygous female mice using KL as a growth factor, the cultures initially contained a mixture of WASP positive and negative populations. KL-driven differentiation into mature BMMCs eventually resulted in homogenous WASP positive cultures derived from the WASP positive progenitors. Thus, WASP expression conferred a selective advantage to the development of Kit-dependent hematopoiesis consistent with the selective advantage of WASP positive blood cells observed in WAS heterozygous female humans. Finally, KL-mediated gene expression in BMMCs derived from WASP negative mice or WT controls was compared and revealed in summary that at least 30% of all changes are WASP-dependent. The results indicate that WASP is downstream of Kit signaling and necessary for Kit-mediated filopodia formation, cell survival and gene expression.