Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:O75695 (X-linked recessive)
2,041 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Skin diseases manifesting classic sex-linked recessive patterns of inheritance provide straightforward problems in the mapping of disease loci. In contrast to autosomal disorders, in which the abnormal gene might be found on any chromosome, sex-linked diseases are found only on the human X chromosome. Thus, with a reasonable number of polymorphic DNA probes and families with living affected and unaffected males, disease loci can be easily mapped to the relevant subregions of the X chromosome. The Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disorder characterized by eczema, immunodeficiency, and thrombocytopenia. Boys with WAS suffer from skin diseases, bleeding problems, recurrent infections, and lymphoid malignancies. In contrast, females who carry the WAS gene are entirely normal, as the abnormal X chromosome is selectively inactivated in cells of hematopoietic origin. Using restriction fragment length polymorphisms (RFLPs) and appropriate families, the WAS locus has been mapped to the proximal portion of the short arm of the X chromosome (Xp11). Prenatal diagnosis is now possible using specific RFLP markers. Moreover, combining RFLP studies with methylation analysis has allowed identification of all female carriers. Although the abnormal gene and protein that are responsible for WAS are currently unknown, studies using yeast artificial chromosomes containing portions of human Xp11 should ultimately allow for the cloning and characterization of the WAS gene. As this gene is expressed primarily in cells of bone marrow origin, WAS is an excellent candidate disease for gene therapy.
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PMID:The Wiskott-Aldrich syndrome. 810 60

We have cloned a segment of the human gene encoding UDP-galactose translocator by genetic complementation of its defective mutant in mouse FM3A cells. Chromosome mapping using fluorescent in situ hybridization revealed that the cloned gene hybridized to the Xp11.23-11.23 region of the X chromosome. This region is shared by the locus of Wiskott-Aldrich syndrome, an X-linked recessive immunodeficiency disorder, characterized by defective sugar chains on cell surface components. Genetic and phenotypic similarities suggest a possible link between UDP-galactose translocator and the Wiskott-Aldrich syndrome (WAS).
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PMID:The UDP-galactose translocator gene is mapped to band Xp11.23-p11.22 containing the Wiskott-Aldrich syndrome locus. 812 16

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

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

Four related male infants presented with neonatal diabetes mellitus, immune dysregulation with extremely high concentrations of immunoglobulin E, and intractable diarrhoea. They were all from one family, and all of them died. As far as is known this X-linked recessive disorder has not been described before. It is suggested that this is a new immunodeficiency in which type 2 T helper responses predominate.
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PMID:X-linked immune dysregulation, neonatal insulin dependent diabetes, and intractable diarrhoea. 894 5

Wiskott-Aldrich syndrome (WAS) is one of the primary immunodeficiency diseases, that is inherited as an X-linked recessive trait. Since the responsible gene, the WASP gene, has been identified, various mutations for patients with WAS have been reported. We found a novel splice-site mutation in a patient with clinically diagnosed WAS. The mutation was a replacement of ag by aa in an acceptor site of intron 2 of the WASP gene. Sequencing studies of the WASP cDNA of the patient revealed that exon 3 of the WASP gene was abnormally missing due to a splicing defect.
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PMID:Detection of a novel splice-site mutation that results in skipping exon 3 of the WASP gene in a patient with Wiskott-Aldrich syndrome. 898 30

The Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disorder described as a clinical triad of thrombocytopenia, eczema, and immunodeficiency. The gene responsible for WAS encodes a 502-amino acid proline-rich protein (WASp) that is likely to play a role in the cytoskeleton reorganization and/or in signal transduction of hematopoietic cells. However, the function and the regulation of the WAS gene (WASP) have not yet been clearly defined. We have studied WASP expression at the transcriptional level in freshly isolated mature peripheral blood cells and during hematopoietic development. For this purpose, we have isolated CD34+ hematopoietic precursor cells from cord blood. These cells were cultured in vitro with various growth factors to generate committed or mature cells belonging to different hematopoietic differentiation pathways, such as granulocytic (CD15+) cells, monocytic (CD14+) cells, dendritic (CD1a+) cells, erythroid lineage (glycophorin A+) cells, and megakaryocytic cells (CD41+). We have shown by reverse transcriptase polymerase chain reaction analysis that the WASP transcript is ubiquitously detectable throughout differentiation from early hematopoietic progenitors, including CD34+CD45RA- and CD34+CD45RA+ cells, to cells belonging to different hematopoietic lineages, including erythroid-committed and dendritic cells. In addition, Northern blot analysis showed that peripheral blood circulating lymphocytes (CD3+ and CD19+ cells) and monocytes express WASP mRNA. Several hematopoietic cell lines were tested and higher levels of expression were consistently detected in myelomonocytic cell types. By contrast, primary nonhematopoietic cells, including fibroblasts, endothelial cells, and keratinocytes, were consistently negative for WASP mRNA.
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PMID:Expression of Wiskott-Aldrich syndrome protein (WASP) gene during hematopoietic differentiation. 920 40

The Wiskott-Aldrich syndrome (WAS) is a rare X-linked recessive disorder characterized by eczema, thrombocytopenia, and immunodeficiency. An allelic variant of the disease is characterized by isolated thrombocytopenia (XLT). The gene responsible for WAS/XLT (WASP) encodes for a 502 amino acid protein (WASP) that is possibly involved in actin binding and cytoskeleton organization. The expression of WASP and the distribution of F-actin and alpha-actinin (which binds to and stabilizes actin filaments) have been analysed in lymphoblastoid cell lines from six patients with WAS and one with XLT. Western blot and immunocytochemistry did not reveal WASP expression in four WAS patients, whereas two WAS patients (with a moderate clinical course) expressed trace amounts of mutant WASP. In contrast, the XLT patient expressed normal amounts of WASP. Furthermore, cell lines from WAS and XLT patients also markedly differed in F-actin polymerization and alpha-actinin distribution. In particular, severe defects of cytoplasmic F-actin expression and of F-actin-positive microvillus formation, and impaired capping of alpha-actinin, were observed in all patients who lacked WASP. As a whole, the degree of impairment of WASP protein expression in WAS/XLT seems to correlate with anomalies of cytoskeletal organization, strongly supporting a role for WASP in the regulation of F-actin polymerization.
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PMID:Defective actin polymerization in EBV-transformed B-cell lines from patients with the Wiskott-Aldrich syndrome. 971 66

Recurrent acyclovir (ACV)-resistant (ACV-r) herpes simplex virus type 1 (HSV-1) infections occurred in a patient with Wiskott-Aldrich syndrome, an X-linked recessive immunodeficiency syndrome composed of three clinical characteristics of immunodeficiency, thrombocytopenia, and an eczematous dermatitis. The patient had severe and recurrent ACV-r herpes simplex and was treated with vidarabine in a satisfactory manner from 1993 to 1997. During the 4-year observation period, two ACV-sensitive (ACV-s) HSV-1 isolates and five ACV-r HSV-1 isolates were recovered. The nucleotide sequence of the thymidine kinase (TK) gene from these sequential ACV-r isolates was compared with the ACV-s isolates. A single nucleotide deletion of cytosine (C) from homopolymer stretch of four C residues between nucleotide 1061 and 1064 of the open reading frame was found in all ACV-r isolates. No other differences were observed in the TK nucleotide sequence between ACV-s and ACV-r isolates. The TK nucleotide sequences of the two ACV-s isolates were identical to each other and those of the five ACV-r isolates were identical to one another. These results suggest that the ACV-r HSV-1 might have derived from the ACV-s strain in the patient body and that TK-associated ACV-r HSV-1 can reactivate from latency.
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PMID:Nucleotide sequence of thymidine kinase gene of sequential acyclovir-resistant herpes simplex virus type 1 isolates recovered from a child with Wiskott-Aldrich syndrome: evidence for reactivation of acyclovir-resistant herpes simplex virus. 1042 6

Wiskott-Aldrich syndrome (WAS) is an X-linked recessive immunodeficiency characterized by thrombocytopenia, eczema, and recurrent infections, and caused by mutations in the WAS protein (WASP) gene. WASP contains several functional domains through which it interacts with proteins involved in intracellular signaling and regulation of the actin cytoskeleton. In this report, 17 WASP gene mutations were identified, 12 of which are novel. DNA of affected males and obligate carriers was PCR amplified and analyzed by SSCA, heteroduplex analysis, and direct sequencing. The effects of the mutations at the mRNA and protein level were ascertained by RT-PCR and Western blot analyses. All missense mutations were located in exons 1-4. Most of the nonsense, frameshift and splice site mutations were found in exons 6-11. Mutations that alter splice sites led to the synthesis of several types of mRNAs, a fraction of which represented the normally spliced product. The presence of normally spliced transcripts was correlated with a milder phenotype. When one such case was studied by Western blotting, reduced amounts of normal-size WASP were present. In other cases as well, a correlation was found between the amount of normal or mutant WASP present and the phenotypes of the affected individuals. No protein was detected in two individuals with severe WAS. Reduced levels of a normal-size WASP with a missense mutation were seen in two individuals with XLT. It is concluded that mutation analysis at the DNA level is not sufficient for predicting clinical course. Studies at the transcript and protein level are needed for a better assessment.
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PMID:Novel mutations in the Wiskott-Aldrich syndrome protein gene and their effects on transcriptional, translational, and clinical phenotypes. 1044 59


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