Genotype-Proteotype Linkage in the Wiskott-Aldrich Syndrome1

@article{Lutskiy2005GenotypeProteotypeLI,
  title={Genotype-Proteotype Linkage in the Wiskott-Aldrich Syndrome1},
  author={Maxim I. Lutskiy and Fred S. Rosen and Eileen Remold-O’Donnell},
  journal={The Journal of Immunology},
  year={2005},
  volume={175},
  pages={1329 - 1336}
}
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… 

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References

SHOWING 1-10 OF 45 REFERENCES
Wiskott-Aldrich syndrome/X-linked thrombocytopenia: WASP gene mutations, protein expression, and phenotype.
TLDR
It is concluded 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 complex mutations affect the 3' portion of WasP interfere with crucial functions ofThe protein and cause classic WAS.
Mutations that cause the Wiskott-Aldrich syndrome impair the interaction of Wiskott-Aldrich syndrome protein (WASP) with WASP interacting protein.
TLDR
Impaired WASP-WIP interaction may contribute to Wiskott-Aldrich syndrome, and point mutant analyses in the two-hybrid system and in vitro show impairment of WasP-wIP interaction with three WASP missense mutants known to cause WAS.
A novel protocol to identify mutations in patients with wiskott-Aldrich syndrome.
TLDR
A simpler protocol, designed for use in clinical settings to identify the mutations of newly diagnosed patients, relies on directly sequencing amplified exons according to a staggered schedule based on statistical evaluation of previous cases and demonstrates the suitability, reliability, and versatility of the new protocol.
Mutations of the Wiskott-Aldrich Syndrome Protein (WASP): hotspots, effect on transcription, and translation and phenotype/genotype correlation.
TLDR
By analyzing a large number of patients with WAS/XLT at the molecular level, 5 mutational hotspots in the WASP gene are identified and a strong association between genotype and phenotype is established.
Novel mutations in the Wiskott‐Aldrich syndrome protein gene and their effects on transcriptional, translational, and clinical phenotypes
TLDR
It is concluded that mutation analysis at the DNA level is not sufficient for predicting clinical course and studies at the transcript and protein level are needed for a better assessment.
Clinical course of patients with WASP gene mutations.
TLDR
It is demonstrated that WAS protein expression is a useful tool for predicting long-term prognosis for patients with WAS/XLT and hematopoietic stem cell transplantation should be considered, especially for WASP-negative patients, while the patients are young to improve prognosis.
Wiskott-Aldrich syndrome in a female.
TLDR
A 14-month-old girl with a history of WAS in her family who presented with thrombocytopenia, small platelets, and immunologic dysfunction has a defect in the mechanisms that lead in disease-free WAS carriers to preferential survival/proliferation of cells bearing the active wild-type X chromosome.
Identification of WASP mutations, mutation hotspots and genotype-phenotype disparities in 24 patients with the Wiskott-Aldrich syndrome
TLDR
Findings reveal a lack of phenotype concordance with genotype in WAS and thus imply that phenotypic outcome in this disease cannot be reliably predicted solely on the basis of WASP genotypes.
The thrombocytopenia of Wiskott Aldrich syndrome is not related to a defect in proplatelet formation.
TLDR
The results suggest that the platelet defect in WAS patients is not due to abnormal platelet production, but instead to cytoskeletal changes occuring in platelets during circulation.
Variable expression of WASP in B cell lines of Wiskott-Aldrich syndrome patients.
TLDR
The findings suggest that the clinical variability of the Wiskott-Aldrich syndrome can partially be explained by the level of WASP protein in the patient's cells.
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