Novel mutations in the Wiskott-Aldrich syndrome protein gene and their effects on transcriptional, translational, and clinical phenotypes

Lemahieu, Vanessa; Gastier, Julie M.; Francke, Uta

doi:10.1002/(sici)1098-1004(1999)14:1<54::aid-humu7>3.0.co;2-e

Cited by 63 publications

(27 citation statements)

References 44 publications

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“…In this survey, we did not analyze WASP gene mutations and protein levels. In previous studies, mutation analysis in typical cases of WAS has suggested that there is a link between clinical phenotype and genotype, 3,16,17 but exceptions have been found. 18,19 All mutations resulting in a mild phenotype (XLT) result in the production of normal-sized or truncated protein in various quantities.…”

Section: Discussionmentioning

confidence: 98%

Autoimmunity in Wiskott-Aldrich Syndrome: Risk Factors, Clinical Features, and Outcome in a Single-Center Cohort of 55 Patients

et al. 2003

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ABSTRACT. Objectives. To evaluate the occurrence of autoimmune and inflammatory complications in Wiskott-Aldrich syndrome (WAS) and to determine risk factors and the prognosis of such complications with the aim of improving the definition of treatment options.Methods. We reviewed the records of 55 patients with WAS evaluated at Necker-Enfants Malades Hospital (Paris) from 1980 to 2000.Results. Forty patients (72%) had at least 1 autoimmune or inflammatory complication. Autoimmune hemolytic anemia was detected in 20 cases (36%); in all cases, onset occurred before the age of 5 years. Other complications included neutropenia (25%), arthritis (29%), skin vasculitis (22%), cerebral vasculitis (7%), inflammatory bowel disease (9%), and renal disease (3%). The median survival of the entire population was 14.5 years. Two autoimmune complications and 1 biological factor were predictive of a poor prognosis in this population: autoimmune hemolytic anemia, severe thrombocytopenia recurring after splenectomy, and high serum immunoglobulin M (IgM) levels before splenectomy. Autoimmune hemolytic anemia was significantly more observed in patients with high serum IgM level.Conclusions. High serum IgM concentration before splenectomy was identified as a risk factor for autoimmune hemolytic anemia; however, it must be confirmed. Autoimmune hemolytic anemia and severe thrombocytopenia recurring after splenectomy were 2 indicators of a poor prognosis. Those results suggest that patients with WAS and IgM levels more than mean ؉ 2 standard deviations before splenectomy should be placed under strict surveillance. Furthermore, severe autoimmune complications should lead, as early as possible, to hematopoietic stem cell transplantation using the best available donor. Pediatrics 2003;111:e622-e627. URL: http://www.pediatrics.org/cgi/content/full/111/5/e622; arthritis, autoimmunity, autoimmune hemolytic anemia, children, hematopoietic stem cell transplantation, immunodeficiency, thrombocytopenia, vasculitis, Wiskott-Aldrich syndrome.ABBREVIATIONS. WAS, Wiskott-Aldrich syndrome; IVIG, intravenous immunoglobulin; IG, immunoglobulin; SD, standard deviation; HSCT, hematopoietic stem cell transplantation; AIHA, autoimmune hemolytic anemia; GVHD, graft-versus-host disease. W iskott-Aldrich syndrome (WAS) is an Xlinked primary immunodeficiency originally described as a clinical triad of immunodeficiency, thrombocytopenia, and eczema. [1][2][3] Many patients express the full triad of clinical manifestations, but others have a milder phenotype and survive to adulthood. Phenotypic expression varies over time in a given patient. 3,4 Patients with autoimmune and inflammatory manifestations usually constitute a high-risk group 4 with poor outcome, but only 2 large retrospective surveys 4,5 have analyzed WAS and complications. We conducted this study in a cohort of patients with WAS to evaluate the occurrence of autoimmune and inflammatory complications at a single center, to define specific subgroups with a poor prognosis, and to identify prognostic f...

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Section: Discussionmentioning

confidence: 98%

Autoimmunity in Wiskott-Aldrich Syndrome: Risk Factors, Clinical Features, and Outcome in a Single-Center Cohort of 55 Patients

et al. 2003

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“…Most notable was patient W21, diagnosed at age 5 years, who has mild disease, suggesting that his variant protein, which lacks half of the proline-rich region (63 aa), retains some degree of normal function. Although we studied only one patient with this mutation, genotype-proteotype linkage is likely because an unrelated family with the same "nonsense" mutation includes three siblings who also have mild disease (scores of 1, 1, and 2) (14). Of note, the less dramatic ameliorating effect of the alternatively spliced WASP variant that lacks 52 aa in the same region may be due to lower expression levels.…”

Section: Discussionmentioning

confidence: 99%

“…Early reports associated missense mutations, which cluster in the EVH1 domain with XLT or mild immune disease (4,13,14) and frameshift, nonsense, and splice site mutations with severe disease (4, 14 -16). However, this linkage was not seen in other studies (17,18), and many exceptions are known.…”

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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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“…The translation of such aberrant mRNA will produce a truncated protein with a premature stop at codon 190. Activation of this cryptic splice site in WASP has already been reported (Lemahieu et al 1999). Specifically, mutation IVS6+5G>A has been shown to alter normal RNA splicing, with the generation of three different transcripts: a major transcript (70%), containing the 38 nucleotides from intron 6; a minor transcript (2%), including the 38 nt insertion and skipping of exon 7; and a normal transcript (28 %), that leads to very reduced levels of normal-sized protein.…”

Section: Discussionmentioning

confidence: 90%

Identification and characterization of a novel splice-site mutation in a patient with Wiskott-Aldrich syndrome

et al. 2003

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Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disorder characterized by immunodeficiency, eczema, and thrombocytopenia with small platelets. A wide spectrum of mutations in the WiskottAldrich syndrome protein (WASP) gene have been identified as causative of the disease. In the present paper, we report on a family with a boy affected by WAS, with a splice-site mutation caused by a T to G substitution in the +2 position of intron 6 (IVS6+2T>G). Expression studies performed in COS-7 and U-937 cells showed that the mutation affected the normal splicing process. As a consequence, an abnormally long transcript of 38 nucleotides is generated. Such missplicing is probably due to the activation of a cryptic splice donor site located 38 nt downstream of exon 6. The translation of such aberrant mRNA will produce a truncated protein with a premature stop at codon 190. Thus, a novel splice-site mutation is reported in a patient with a mild WAS phenotype.

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Novel mutations in the Wiskott-Aldrich syndrome protein gene and their effects on transcriptional, translational, and clinical phenotypes

Cited by 63 publications

References 44 publications

Autoimmunity in Wiskott-Aldrich Syndrome: Risk Factors, Clinical Features, and Outcome in a Single-Center Cohort of 55 Patients

Autoimmunity in Wiskott-Aldrich Syndrome: Risk Factors, Clinical Features, and Outcome in a Single-Center Cohort of 55 Patients

Genotype-Proteotype Linkage in the Wiskott-Aldrich Syndrome

Identification and characterization of a novel splice-site mutation in a patient with Wiskott-Aldrich syndrome

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