Clinical course of patients with WASP gene mutations

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

Blood ◽

10.1182/blood.v90.7.2680 ◽

1997 ◽

Vol 90 (7) ◽

pp. 2680-2689 ◽

Cited By ~ 169

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.

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

Thrombosis and Haemostasis ◽

10.1055/s-0038-1650318 ◽

1996 ◽

Vol 75 (04) ◽

pp. 546-550 ◽

Cited By ~ 21

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.

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

Blood ◽

10.1182/blood.v86.10.3797.bloodjournal86103797 ◽

1995 ◽

Vol 86 (10) ◽

pp. 3797-3804 ◽

Cited By ~ 150

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.

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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 Protein (WASP) Is An Effector of Kit Signaling.

Blood ◽

10.1182/blood.v112.11.1410.1410 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1410-1410

Author(s):

Maheswaran Mani ◽

Shivkumar Venkatasubrahmanyam ◽

Mrinmoy Sanyal ◽

Yujun Yang ◽

Jing Huang ◽

...

Keyword(s):

Gene Expression ◽

Progenitor Cells ◽

Blood Cells ◽

Selective Advantage ◽

Calcium Flux ◽

Heterozygous Female ◽

Hematopoietic Stem ◽

Actin Reorganization ◽

Wiskott Aldrich Syndrome ◽

Wasp Gene

Abstract 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.

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

Human Genetics ◽

10.1007/s004390050162 ◽

1996 ◽

Vol 98 (1) ◽

pp. 68-76 ◽

Cited By ~ 53

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

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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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Correlation between ETFDH mutations and dysregulation of serum myomiRs in MADD patients

European Journal of Translational Myology ◽

10.4081/ejtm.2019.8880 ◽

2020 ◽

Vol 30 (1) ◽

pp. 116-120 ◽

Cited By ~ 1

Author(s):

Sara Missaglia ◽

Valentina Pegoraro ◽

Roberta Marozzo ◽

Daniela Tavian ◽

Corrado Angelini

Keyword(s):

Fatty Acids ◽

Electron Transfer ◽

Early Onset ◽

Dehydrogenase Deficiency ◽

Frameshift Mutation ◽

Late Onset ◽

Clinical Phenotype ◽

Gene Mutations ◽

Compound Heterozygote ◽

Missense Mutations

Multiple acyl-CoA dehydrogenase deficiency (MADD) is a rare fatty acids oxidation disorder which is often associated with deficiency of electron transfer flavoprotein dehydrogenase (ETFDH). In this study we reported clinical features and evaluation of expression profile of circulating muscle-specific miRNAs (myomiRs) in two MADD patients carrying different ETFDH gene mutations. Patient 1 was a compound heterozygote for two missense mutations. She showed a late onset MADD clinical phenotype and a significant increase of serum myomiRs. Patient 2, carrying a missense and a frameshift mutation, displayed early onset symptoms and a slight increase of some serum myomiRs.

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