Specificities of the course of Wiscott-Aldrich syndrome depending on WASP gene mutations

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.

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

Human Mutation ◽

10.1002/(sici)1098-1004(200004)15:4<386::aid-humu24>3.0.co;2-1 ◽

2000 ◽

Vol 15 (4) ◽

pp. 386-387 ◽

Cited By ~ 7

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

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

Blood ◽

10.1182/blood.v90.7.2680.2680_2680_2689 ◽

1997 ◽

Vol 90 (7) ◽

pp. 2680-2689 ◽

Cited By ~ 7

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.

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Clinical course of patients with WASP gene mutations

Blood ◽

10.1182/blood-2003-05-1480 ◽

2004 ◽

Vol 103 (2) ◽

pp. 456-464 ◽

Cited By ~ 227

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.

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

Human Molecular Genetics ◽

10.1093/hmg/4.7.1127 ◽

1995 ◽

Vol 4 (7) ◽

pp. 1127-1135 ◽

Cited By ~ 107

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

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

LymphoSign Journal ◽

10.14785/lymphosign-2021-0022 ◽

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.

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