Mutations of the Wiskott-Aldrich Syndrome Protein (WASP): hotspots, effect on transcription, and translation and phenotype/genotype correlation

Jin, Yinzhu; Mazza, Cinzia; Christie, Jacinda R.; Giliani, Silvia; Fiorini, Maurilia; Mella, Patrizia; Gandellini, Francesca; Stewart, Dawn; Zhu, Qili; Nelson, David L.; Notarangelo, Luigi D.; Ochs, Hans D.

doi:10.1182/blood-2003-05-1592

Cited by 292 publications

(305 citation statements)

References 42 publications

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“…Knowledge of the molecular effect of mutations provides a logical basis for correlating genotype and clinical phenotype. The value of this information was enhanced recently by two large studies that correlated WASP proteotype and clinical outcome (42,43). A comprehensive analysis of clinical data collected longitudinally for a panel of 50 Japanese patients found that several important markers of clinical phenotype correlated with presence or absence of WASP (43).…”

Section: Discussionmentioning

confidence: 99%

Genotype-Proteotype Linkage in the Wiskott-Aldrich Syndrome

Lutskiy

Rosen

Remold‐O′Donnell

2005

The Journal of Immunology

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Wiskott-Aldrich syndrome (WAS) is a platelet/immunodeficiency disease arising from mutations of WAS protein (WASP), a hemopoietic cytoskeletal protein. Clinical symptoms vary widely from mild (X-linked thrombocytopenia) to life threatening. In this study, we examined the molecular effects of individual mutations by quantifying WASP in peripheral lymphocytes of 44 patients and identifying the molecular variant (collectively called proteotype). Nonpredicted proteotypes were found for 14 genotypes. These include WASP-negative lymphocytes found for five missense genotypes and WASP-positive lymphocytes for two nonsense, five frameshift, and two splice site genotypes. Missense mutations in the Ena/VASP homology 1 (EVH1) domain lead to decreased/absent WASP but normal mRNA levels, indicating that proteolysis causes the protein deficit. Because several of the EVH1 missense mutations alter WIP binding sites, the findings suggest that abrogation of WIP binding induces proteolysis. Whereas platelets of most patients were previously shown to lack WASP, WASP-positive platelets were found for two atypical patients, both of whom have mutations outside the EVH1 domain. WASP variants with alternative splicing and intact C-terminal domains were characterized for eight nonsense and frameshift genotypes. One of these, a nonsense genotype in a mild patient, supports expression of WASP lacking half of the proline-rich region. With one notable exception, genotype and proteotype were linked, indicating that a genotype-proteotype registry could be assembled to aid in predicting disease course and planning therapy for newly diagnosed infants. Knowledge of the molecular effect of mutations would aid also in identifying disease-modifying genes.

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Section: Discussionmentioning

confidence: 99%

Genotype-Proteotype Linkage in the Wiskott-Aldrich Syndrome

Lutskiy

Rosen

Remold‐O′Donnell

2005

The Journal of Immunology

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“…They are distributed throughout the gene and include missense, nonsense, and frameshift mutations, and insertions, deletions, and mutations of splice sites. [13][14][15] They invariably lead to reduced or completely absent WASp levels and/or activity and diminished actin polymerization in hematopoietic cells. 16 As a result, many aspects of hematologic and immune cell function are abrogated, including cell signaling, migration, and phagocytosis.…”

Section: Introductionmentioning

confidence: 99%

Two novel activating mutations in the Wiskott-Aldrich syndrome protein result in congenital neutropenia

Ancliff

Blundell

Cory

et al. 2006

Blood

202

222

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“…Most missense mutations in patients with WAS and X-linked thrombocytopenia are localized to the WIP binding EVH1 domain of WASP (12,14). In fact, three of these mutations, R86H, Y107C, and A134T, which affect residues that are predicted by NMR studies to be contact points for WIP, were shown to disrupt WIP binding (15).…”

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confidence: 99%

WIP is a chaperone for Wiskott–Aldrich syndrome protein (WASP)

Fuente

Sasahara

Calamito

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Wiskott–Aldrich syndrome protein (WASP) is in a complex with WASP-interacting protein (WIP). WASP levels, but not mRNA levels, were severely diminished in T cells from WIP −/− mice and were increased by introduction of WIP in these cells. The WASP binding domain of WIP was shown to protect WASP from degradation by calpain in vitro . Treatment with the proteasome inhibitors MG132 and bortezomib increased WASP levels in T cells from WIP −/− mice and in T and B lymphocytes from two WAS patients with missense mutations (R86H and T45M) that disrupt WIP binding. The calpain inhibitor calpeptin increased WASP levels in activated T and B cells from the WASP patients, but not in primary T cells from the patients or from WIP −/− mice. Despite its ability to increase WASP levels proteasome inhibition did not correct the impaired IL-2 gene expression and low F-actin content in T cells from the R86H WAS patient. These results demonstrate that WIP stabilizes WASP and suggest that it may also be important for its function.

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Mutations of the Wiskott-Aldrich Syndrome Protein (WASP): hotspots, effect on transcription, and translation and phenotype/genotype correlation

Cited by 292 publications

References 42 publications

Genotype-Proteotype Linkage in the Wiskott-Aldrich Syndrome

Genotype-Proteotype Linkage in the Wiskott-Aldrich Syndrome

Two novel activating mutations in the Wiskott-Aldrich syndrome protein result in congenital neutropenia

WIP is a chaperone for Wiskott–Aldrich syndrome protein (WASP)

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