scholarly journals Wiskott-Aldrich Syndrome/X-Linked Thrombocytopenia: WASP Gene Mutations, Protein Expression, and Phenotype

Blood ◽  
1997 ◽  
Vol 90 (7) ◽  
pp. 2680-2689 ◽  
Author(s):  
Qili Zhu ◽  
Chiaki Watanabe ◽  
Ting Liu ◽  
Diane Hollenbaugh ◽  
R. Michael Blaese ◽  
...  
Keyword(s):  
Splice Site ◽  
Gene Mutations ◽  
Missense Mutations ◽  
Ph Domain ◽  
Glutathione S Transferase ◽  
Mild Phenotype ◽  
Wiskott Aldrich Syndrome ◽  
Mild Disease ◽  
Exon 4 ◽  
Wasp Gene

Wiskott-Aldrich syndrome (WAS) and X-linked thrombocytopenia (XLT), caused by mutations of the WAS protein (WASP) gene, represent different phenotypes of the same disease. To demonstrate a phenotype/genotype correlation, we determined WASP gene mutations in 48 unrelated WAS families. Mutations included missense (20 families) and nonsense (eight) mutations located mostly in exons 1 to 4, and splice-site mutations (seven) and deletions and insertions (13) located preferentially in exons 7 to 11. Both genomic DNA and cDNA were sequenced and WASP expression was measured in cell lysates using peptide-specific rabbit anti-WASP antibodies. WASP was expressed in hematopoietic cell lines including bone marrow–derived CD34+ cells. Missense mutations located in exons 1 to 3 caused mild disease in all but one family and permitted WASP expression, although frequently at decreased concentration. Missense mutations affecting exon 4 were associated with classic WAS and, with one exception, barely detectable WASP. Nonsense mutations caused classic WAS and lack of protein. Insertions, deletions, and splice-site mutations resulted in classic WAS and absent, unstable, truncated, or multiply spliced protein. Using affinity precipitation, WASP was found to bind to Src SH3-containing proteins Fyn, Lck, PLC-γ, and Grb2, and mutated WASP, if expressed, was able to bind to Fyn-glutathione S-transferase (GST) fusion protein. We conclude that missense mutations affecting the PH domain (exons 1 to 3) of WASP inhibit less important functions of the protein and result in a mild phenotype, and that missense mutations affecting exon 4 and complex mutations affecting the 3′ portion of WASP interfere with crucial functions of the protein and cause classic WAS.

scholarly journals Wiskott-Aldrich Syndrome/X-Linked Thrombocytopenia: WASP Gene Mutations, Protein Expression, and Phenotype

Blood ◽  
1997 ◽  
Vol 90 (7) ◽  
pp. 2680-2689 ◽  
Author(s):  
Qili Zhu ◽  
Chiaki Watanabe ◽  
Ting Liu ◽  
Diane Hollenbaugh ◽  
R. Michael Blaese ◽  
...  
Keyword(s):  
Splice Site ◽  
Gene Mutations ◽  
Missense Mutations ◽  
Ph Domain ◽  
Glutathione S Transferase ◽  
Mild Phenotype ◽  
Wiskott Aldrich Syndrome ◽  
Mild Disease ◽  
Exon 4 ◽  
Wasp Gene

Abstract Wiskott-Aldrich syndrome (WAS) and X-linked thrombocytopenia (XLT), caused by mutations of the WAS protein (WASP) gene, represent different phenotypes of the same disease. To demonstrate a phenotype/genotype correlation, we determined WASP gene mutations in 48 unrelated WAS families. Mutations included missense (20 families) and nonsense (eight) mutations located mostly in exons 1 to 4, and splice-site mutations (seven) and deletions and insertions (13) located preferentially in exons 7 to 11. Both genomic DNA and cDNA were sequenced and WASP expression was measured in cell lysates using peptide-specific rabbit anti-WASP antibodies. WASP was expressed in hematopoietic cell lines including bone marrow–derived CD34+ cells. Missense mutations located in exons 1 to 3 caused mild disease in all but one family and permitted WASP expression, although frequently at decreased concentration. Missense mutations affecting exon 4 were associated with classic WAS and, with one exception, barely detectable WASP. Nonsense mutations caused classic WAS and lack of protein. Insertions, deletions, and splice-site mutations resulted in classic WAS and absent, unstable, truncated, or multiply spliced protein. Using affinity precipitation, WASP was found to bind to Src SH3-containing proteins Fyn, Lck, PLC-γ, and Grb2, and mutated WASP, if expressed, was able to bind to Fyn-glutathione S-transferase (GST) fusion protein. We conclude that missense mutations affecting the PH domain (exons 1 to 3) of WASP inhibit less important functions of the protein and result in a mild phenotype, and that missense mutations affecting exon 4 and complex mutations affecting the 3′ portion of WASP interfere with crucial functions of the protein and cause classic WAS.

Clinical course of patients with WASP gene mutations

Blood ◽  
2004 ◽  
Vol 103 (2) ◽  
pp. 456-464 ◽  
Author(s):  
Kohsuke Imai ◽  
Tomohiro Morio ◽  
Yi Zhu ◽  
Yinzhu Jin ◽  
Sukeyuki Itoh ◽  
...  
Keyword(s):  
Clinical Phenotype ◽  
Pneumocystis Carinii ◽  
Gene Mutations ◽  
Japanese Patients ◽  
Severe Form ◽  
Missense Mutations ◽  
Hematopoietic Stem ◽  
Wiskott Aldrich Syndrome ◽  
Wasp Gene ◽  
Genotype Correlation

Abstract Mutations of the Wiskott-Aldrich syndrome protein (WASP) gene result either in the classic Wiskott-Aldrich syndrome (WAS) or in a less severe form, X-linked thrombocytopenia (XLT). A phenotype-genotype correlation has been reported by some but not by other investigators. In this study, we characterized WASP gene mutations in 50 Japanese patients and analyzed the clinical phenotype and course of each. All patients with missense mutations were WASP-positive. In contrast, patients with nonsense mutations, large deletions, small deletions, and small insertions were WASP-negative. Patients with splice anomalies were either WASP-positive or WASP-negative. The clinical phenotype of each patient was correlated with the presence or absence of WASP. Lack of WASP expression was associated with susceptibility to bacterial, viral, fungal, and Pneumocystis carinii infections and with severe eczema, intestinal hemorrhage, death from intracranial bleeding, and malignancies. Rates for overall survival and survival without intracranial hemorrhage or other serious complications were significantly lower in WASP-negative patients. This analysis provides evidence for a strong phenotype-genotype correlation and demonstrates that WAS protein expression is a useful tool for predicting long-term prognosis for patients with WAS/XLT. Based on data presented here, hematopoietic stem cell transplantation should be considered, especially for WASP-negative patients, while the patients are young to improve prognosis.

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

2021 ◽  
Author(s):  
Jenny Garkaby ◽  
Julia Upton
Keyword(s):  
Gene Sequence ◽  
Novel Mutation ◽  
Gene Mutations ◽  
Good Health ◽  
Genetic Mutation ◽  
Mild Phenotype ◽  
Wiskott Aldrich Syndrome ◽  
Gene Sequence Analysis ◽  
Increased Risk ◽  
Wasp Gene

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.

Mutation Spectrum in Patients with Wiskott-Aldrich Syndrome and X-linked Thrombocytopenia: Identification of Twelve Different Mutations in the WASP Gene

1996 ◽  
Vol 75 (04) ◽  
pp. 546-550 ◽  
Author(s):  
Marianne Schwartz ◽  
Albert Békássy ◽  
Mikael Donnér ◽  
Thomas Hertel ◽  
Stefan Hreidarson ◽  
...  
Keyword(s):  
Base Pair ◽  
Hot Spot ◽  
Missense Mutations ◽  
Nucleotide Substitutions ◽  
Exon 2 ◽  
Wiskott Aldrich Syndrome ◽  
Base Pair Deletion ◽  
Reliable Diagnosis ◽  
Wasp Gene ◽  
Detection Of Mutations

SummaryTwelve different mutations in the WASP gene were found in twelve unrelated families with Wiskott-Aldrich syndrome (WAS) or X-linked thrombocytopenia (XLT). Four frameshift, one splice, one nonsense mutation, and one 18-base-pair deletion were detected in seven patients with WAS. Only missense mutations were found in five patients diagnosed as having XLT. One of the nucleotide substitutions in exon 2 (codon 86) results in an Arg to Cys replacement. Two other nucleotide substitutions in this codon, R86L and R86H, have been reported previously, both giving rise to typical WAS symptoms, indicating a mutational hot spot in this codon. The finding of mutations in the WASP gene in both WAS and XLT gives further evidence of these syndromes being allelic. The relatively small size of the WASP gene facilitates the detection of mutations and a reliable diagnosis of both carriers and affected fetuses in families with WAS or XLT.

scholarly journals The Wiskott-Aldrich syndrome and X-linked congenital thrombocytopenia are caused by mutations of the same gene

Blood ◽  
1995 ◽  
Vol 86 (10) ◽  
pp. 3797-3804 ◽  
Author(s):  
Q Zhu ◽  
M Zhang ◽  
RM Blaese ◽  
JM Derry ◽  
A Junker ◽  
...  
Keyword(s):  
Clinical Symptoms ◽  
Point Mutations ◽  
Gene Mutations ◽  
Exon Skipping ◽  
Splice Site Mutation ◽  
Missense Mutations ◽  
Site Mutation ◽  
Exon 2 ◽  
Wiskott Aldrich Syndrome ◽  
Was Gene

The Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disorder characterized by thrombocytopenia, small platelets, eczema, recurrent infections, and immunodeficiency. Besides the classic WAS phenotype, there is a group of patients with congenital X-linked thrombocytopenia (XLT) who have small platelets but only transient eczema, if any, and minimal immune deficiency. Because the gene responsible for WAS has been sequenced, it was possible to correlate the WAS phenotypes with WAS gene mutations. Using a fingerprinting screening technique, we determined the approximate location of the mutation in 13 unrelated WAS patients with mild to severe clinical symptoms. Direct sequence analysis of cDNA and genomic DNA obtained from patient-derived cell lines showed 12 unique mutations distributed throughout the WAS gene, including insertions, deletions, and point mutations resulting in amino acid substitutions, termination, exon skipping, or splicing defects. Of 4 unrelated patients with the XLT phenotype, 3 had missense mutations affecting exon 2 and 1 had a splice-site mutation affecting exon 9. Patients with classic WAS had more complex mutations, resulting in termination codons, frameshift, and early termination. These findings provide direct evidence that XLT and WAS are caused by mutations of the same gene and suggest that severe clinical phenotypes are associated with complex mutations.

scholarly journals Identification of six novel WASP gene mutations in patients suffering from Wiskott-Aldrich syndrome

2000 ◽  
Vol 15 (4) ◽  
pp. 386-387 ◽  
Author(s):  
Rik A. Brooimans ◽  
Adri�nne J.A.M van den Berg ◽  
Rienk Y.J. Tamminga ◽  
Tom Revesz ◽  
Nico M. Wulffraat ◽  
...  
Keyword(s):  
Gene Mutations ◽  
Wiskott Aldrich Syndrome ◽  
Wasp Gene

Wiskott-Aldrich syndrome: no strict genotype-phenotype correlations but clustering of missense mutations in the amino-terminal part of the WASP gene product

1996 ◽  
Vol 98 (1) ◽  
pp. 68-76 ◽  
Author(s):  
Dirk Schindelhauer ◽  
Michael Weiss ◽  
Heide Hellebrand ◽  
Astrid Golla ◽  
Martin Hergersberg ◽  
...  
Keyword(s):  
Gene Product ◽  
Missense Mutations ◽  
Terminal Part ◽  
Wiskott Aldrich Syndrome ◽  
Amino Terminal ◽  
Wasp Gene

WASP gene mutations in Wiskott-Aldrich syndrome and X-linked thrombocytopenia

1995 ◽  
Vol 4 (7) ◽  
pp. 1127-1135 ◽  
Author(s):  
J. M. J. Derry ◽  
J. A. Kerns ◽  
K. I. Weinberg ◽  
H. D. Ochs ◽  
V. Volpini ◽  
...  
Keyword(s):  
Gene Mutations ◽  
Wiskott Aldrich Syndrome ◽  
Wasp Gene

scholarly journals High prevalence of nonsense, frame shift, and splice-site mutations in 16 patients with full-blown Wiskott-Aldrich syndrome

Blood ◽  
1995 ◽  
Vol 86 (10) ◽  
pp. 3648-3654 ◽  
Author(s):  
GS Wengler ◽  
LD Notarangelo ◽  
S Berardelli ◽  
G Pollonni ◽  
P Mella ◽  
...  
Keyword(s):  
Splice Site ◽  
Positional Cloning ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Poor Quality ◽  
Wiskott Aldrich Syndrome ◽  
Frame Shift ◽  
Screening Protocol ◽  
Wasp Gene ◽  
Severe Eczema

Wiskott-Aldrich syndrome (WAS) is a fully penetrant X-linked recessive disorder characterized by immunodeficiency, thrombocytopenia, and severe eczema. WAS is a life-threatening disease, with a poor quality of life and high mortality rate in childhood. The gene responsible for the disease has been localized to the proximal short arm of the X- chromosome and recently isolated through positional cloning and named WAS protein (WASP). We have characterized 17 WAS families. We have developed a rapid, nonradioactive screening protocol for identifying WASP gene alterations in genomic DNA. Our method allows simultaneous evaluation of single strand confirmation polymorphism and heteroduplex formation. We have identified 15 novel mutations that involve single basepair changes, or small insertions or deletions, all of which result in premature stop cordon, frame shift with secondary premature stop codon, or splice site defect. These studies document the considerable heterogeneity of the location of mutations in the WASP gene causing full-blown WAS and show the efficiency and rapidity of a screening approach for mutation identification in WAS that will be useful for carrier detection and prenatal diagnosis.

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