Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q00604 (X-linked)
 16,883 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Wiskott-Aldrich syndrome (WAS) is a severe X-linked, recessive disorder, with a high mortality rate at early age due to hemorrhages, infections, and lymphoid malignancies. The molecular pathogenesis of the disease is unknown. Carrier females of WAS are clinically and immunologically normal, thus precluding carrier detection by simple laboratory tests. Major advances in molecular genetics have allowed mapping of the WAS gene to the pericentromeric short arm of the X chromosome, and have made carrier detection and prenatal diagnosis feasible by segregation analysis with closely linked polymorphic DNA markers. Furthermore, the observation that carriers of WAS exhibit a unilateral inactivation of the X chromosome in hematopoietic cells has provided a new tool for carrier detection. However, critical interpretation of molecular analysis data is essential to provide accurate genetic counseling to WAS families.
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PMID:Application of molecular analysis to genetic counseling in the Wiskott-Aldrich syndrome (WAS). 839 23

Several congenital immunodeficiency diseases can exhibit X-linked inheritance, including agammaglobulinemia, severe combined immunodeficiency, Wiskott-Aldrich syndrome, X-linked lymphoproliferative syndrome, and X-linked hyper-IgM syndrome. To date, the gene defects causing each of these X-linked immunodeficiencies have not been identified, and the pathogenic mechanisms whereby mutations in these genes result in immunodeficiency are obscure. Although rare, all are associated with severe infections from early life and high morbidity and mortality. Regional localization of each of these gene defects on the X chromosome has made possible carrier detection and prenatal diagnosis by linkage with polymorphic X chromosome markers in pedigrees demonstrating clear X-linked recessive inheritance. However, without a positive family history, it may not be possible to distinguish clinically between X-linked and autosomal forms. As a partial solution to this problem, it has now been established that female carriers of X-linked agammaglobulinemia, X-severe combined immunodeficiency, and Wiskott-Aldrich syndrome can be identified by the pattern of X chromosome inactivation in cell lineages targeted by each gene defect. As more families are offered the opportunity to use carrier detection and prenatal diagnosis, their decisions will reflect not only their personal experience with affected children with immunodeficiency, but also the clinical advances in bone marrow transplantation and immunomodulation.
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PMID:Prenatal diagnosis and genetic analysis of X-linked immunodeficiency disorders. 843 72

Mutation in the gene encoding the recently isolated WASP protein has now been identified as the genetic defect responsible for the X-linked Wiskott-Aldrich syndrome (WAS), a primary immunodeficiency disease associated with extensive phenotypic variability. To elucidate the range of WASP mutations responsible for WAS, we used PCR-SSCP analysis to screen for WASP gene mutation in 19 unrelated boys with the diagnosis of classical or attenuated WAS or isolated thrombocytopenia. All 19 patients had WASP mutations, each of which localized to the initial three or terminal three exons of the gene, and the majority of which were unique in each case. However, a missense mutation which results in substitution of the arginine at WAS codon 86 was identified in three boys with severe WAS as well as in one boy presenting with thrombocytopenia alone. While the three mutations found in the isolated thrombocytopenia patients leave the reading frame intact, about one-half of the gene alterations detected in both severe and attenuated WAS patients result in frameshifted transcript and premature translation termination. These findings therefore confirm the association of WAS with WASP mutation and identify WASP mutation as a cause for isolated congenital thrombocytopenia in males. While the WASP gene defects responsible for isolated thrombocytopenia and other mild presentations of WAS do not appear distinct from those resulting in severe WAS, these data indicate that analysis of WASP gene mutation provides a valuable tool for distinguishing the spectrum of WAS patients and the subset of males with isolated thrombocytopenia who represent mild cases of WAS.
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PMID:Identification of WASP mutations in patients with Wiskott-Aldrich syndrome and isolated thrombocytopenia reveals allelic heterogeneity at the WAS locus. 852 98

The WASP gene has been recently cloned from Xp11.23 and shown to be mutated in three patients with the Wiskott-Aldrich syndrome (WAS). We have developed a screening protocol for identifying WASP gene alterations in genomic DNA and have identified a spectrum of novel mutations in 12 additional unrelated families. These missense, nonsense and frameshift mutations involve eight of the 12 exons of the gene. Two mutations creating premature termination codons were associated with lack of detectable mRNA on Northern blots. Four amino acid substitutions, Leu27Phe, Thr48Ile, Val75Met and Arg477Lys, were found in patients with congenital thrombocytopenia and no clinically evident immune defect indicating that the WASP gene is the site for mutations in X-linked thrombocytopenia as well as in WAS. A T-cell line from a WAS patient contained two independent DNA alterations, a constitutional frameshift mutation, also present in peripheral blood leukocytes from the patient, and compensatory splice site mutation unique to the cell line. The distribution of eight missense mutations provides valuable information on amino acids which are essential for normal protein function, and suggests that sites in the first two exons are hot-spots for mutation.
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PMID:WASP gene mutations in Wiskott-Aldrich syndrome and X-linked thrombocytopenia. 852 99

We report two sisters in a family representing manifestations of Wiskott-Aldrich syndrome (WAS), an X-linked immunodeficiency disorder. An elder sister had suffered from recurrent infections, small thrombocytopenic petechiae, purpura, and eczema for 7 years. The younger sister had the same manifestations as the elder sister's for a 2-year period, and died of intracranial bleeding at age 2 years. All the laboratory data of the two patients were compatible with WAS, although they were females. Sialophorin analysis with the selective radioactive labeling method of this protein revealed that in the elder sister a 115-KD band that should be specific for sialophorin was reduced in quantity, and instead an additional 135-KD fragment was present as a main band. Polymerase chain reaction (PCR) analysis of the sialophorin gene and single-strand conformation polymorphism (SSCP) analysis of the PCR product demonstrated that there were no detectable size-change nor electrophoretic mobility change in the DNA from both patients. The results indicated that their sialophorin gene structure might be normal. Studies on the mother-daughter transmission of X chromosome using a pERT84-MaeIII polymorphic marker mapped at Xp21 and HPRT gene polymorphism at Xq26 suggested that each sister had inherited a different X chromosome from the mother. Two explanations are plausible for the occurrence of the WAS in our patients: the WAS in the patients is attributable to an autosomal gene mutation which may regulate the sialophorin gene expression through the WAS gene, or, alternatively, the condition in this family is an autosomal recessive disorder separated etiologically from the X-linked WAS.
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PMID:Two sisters with clinical diagnosis of Wiskott-Aldrich syndrome: is the condition in the family autosomal recessive? 912 30

The murine X-linked lymphoproliferative disease scurfy is similar to the Wiskott-Aldrich syndrome in humans. Disease in scurfy (sf) mice is mediated by CD4+ T cells. Based on similarities in scurfy mice and transgenic mice that overexpress specific cytokine genes, we evaluated the expression of cytokines in the lesions of sf mice by Northern blotting, quantitative reverse-transcription polymerase chain reaction (RT-PCR) and by hybridization in situ. Overall, the phenotypic characteristics of scurfy disease correlated well with increased interleukin (IL)-4 (lymphadenopathy), IL-6 (B cell proliferation, hypergammaglobulinemia), IL-7 (dermal inflammatory cell infiltration), and high levels of tumor necrosis factor-alpha (wasting).
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PMID:Disease in the scurfy (sf) mouse is associated with overexpression of cytokine genes. 856 60

The Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disorder originally described as a clinical triad of thrombocytopenia with small platelets, eczema, and immunodeficiency. Impaired CD43 glycoprotein expression on lymphocytes is a typical hallmark of this disorder. The CD43 gene is located on chromosome 16, and the WAS gene, WASP, was recently isolated from the chromosome X p11.22-p11.23. This gene, mutated in WAS patients, encodes a protein that is likely to play a role in controlling the expression of CD43. However, the molecular mechanism(s) causing WAS are not yet known. Herein, we describe a three-generation family in which clinical and laboratory WAS features were expressed in six of nine subjects available for study. At variance with classic X-linked WAS, this disorder was characterized by the presence of thrombocytopenia with a broad spectrum of platelet size, including giant platelets, and was inherited as an autosomal dominant trait. This last finding led us to hypothesize a mutation of the CD43 gene. However, Southern blot analysis failed to detect structural abnormalities of this gene, and genotype analysis ruled out the possibility that a CD43 allele might be shared by the affected individuals. These findings indicate that an alteration(s) of an autosomal gene distinct from the CD43 gene is responsible for the disease. Thus, results from this family, providing the first observation of an autosomally transmitted WAS variant, indicate that genetic mechanism(s) leading to WAS are more complex than previously recognized.
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PMID:Wiskott-Aldrich syndrome: report of an autosomal dominant variant. 863 21

Wiskott-Aldrich syndrome (WAS) is an X-linked immunodeficiency disorder with the most severe pathology in the T lymphocytes and platelets. The disease arises from mutations in the gene encoding the WAS protein. T lymphocytes of affected males with WAS exhibit a severe disturbance of the actin cytoskeleton, suggesting that the WAS protein could regulate its organization. We show here that WAS protein interacts with a member of the Rho family of GTPases, Cdc42. This interaction, which is guanosine 5'-triphosphate (GTP)-dependent, was detected in cell lysates, in transient transfections and with purified recombinant proteins. A weaker interaction was also detected with Rac1 using WAS protein from cell lysates. It was also found that different mutant WAS proteins from three affected males retained their ability to interact with Cdc42 and that the level of expression of the WAS protein in these mutants was only 2-5% of normal. Taken together these data suggest that the WAS protein might function as a signal transduction adaptor downstream of Cdc42, and in affected males, the cytoskeletal abnormalities may result from a defect in Cdc42 signaling.
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PMID:Direct interaction of the Wiskott-Aldrich syndrome protein with the GTPase Cdc42. 864 25

The Wiskott-Aldrich syndrome (WAS) is an X-linked disorder characterized by thrombocytopenia, eczema, disorders in cell-mediated and humoral immunity, and a proclivity to lymphoproliferative disease. The gene responsible encodes a 53-kD proline-rich protein of unknown function (WASP). We produced a FLAG-WASP fusion protein that was used to immunize mice and produce mAbs against WASP. Using monoclonal anti-WASP in Western immunoblots, we have determined that WASP is present in the cytoplasmic but not nuclear fraction of normal human peripheral blood mononuclear cells, in normal human platelets, in T lymphocytes, non-T lymphocytes, and monocytes. The protein is produced in the B cell immunoblastic cell line DS-1, in normal EBV-transformed B cell lines, and in HEL92.1.7, but is barely detectable in MOLT-4 and not detectable in K562. WASP was present in two of four EBV-transformed cell lines from WAS patients. Splenic tissue immunostaining was performed in two patients, and the results correlated with the results of the Western blots. Sequence analysis of WASP cDNA from two patients who produce WASP show mutations causing amino acid substitutions. These studies establish a foundation for further studies aimed at understanding the function of WASP.
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PMID:Studies of the expression of the Wiskott-Aldrich syndrome protein. 864 31

The Wiskott-Aldrich syndrome protein (WASP) gene was found to be mutated in patients presenting with WAS and in patients showing X-linked thrombocytopenia. Mutation analysis in 19 families of German, Swiss and Turkish descent by single-strand conformation polymorphism and sequencing resulted in the detection of seven novel and 10 known mutations. A striking clustering of missense mutations in the first four exons contrasted with a random distribution of nonsense mutations. More than 85% of all known missense mutations were localized in the amino-terminal stretch of the WASP gene product; this region contained a mutational hot spot at codon 86. No genotype-phenotype correlation emerged after a comparison of the identified mutations with the resulting clinical picture for a classical WAS phenotype. A substitution at codon 86 resulted in an extremely variable expression of the disease in a large Swiss family. An extended homology search revealed a distant relationship of this stretch to the vasodilator-stimulated phosphoprotein (VASP), which is involved in the maintenance of cyto-architecture by interacting with actin-like filaments.
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PMID:Wiskott-Aldrich syndrome: no strict genotype-phenotype correlations but clustering of missense mutations in the amino-terminal part of the WASP gene product. 868 10


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