WAS – Thrombocytopenia 1

The Wiskott-Aldrich syndrome protein (WASP), encoded by the WAS gene, is a hematopoietic-specific regulator of actin polymerization required for normal platelet formation. X-linked thrombocytopenia (Thrombocytopenia 1) is an allelic, X-linked recessive variant of Wiskott-Aldrich syndrome characterized by congenital thrombocytopenia with small platelets and minimal immunodeficiency (PMID:14981635). The disease is catalogued as Thrombocytopenia 1.

Inheritance is X-linked recessive, with >250 affected males reported across >70 unrelated families showing perfect cosegregation of WAS variants and thrombocytopenia (PMID:8528199; PMID:7795648). Segregation analysis in extended pedigrees identified at least 19 affected relatives with hemizygous mutations in the WAS gene.

The mutational spectrum comprises >140 distinct variants: ~90 missense substitutions clustered in the WH1 (EVH1) and GBD domains, and ~50 predicted loss-of-function variants including nonsense, frameshift, splice-site, and small insertions/deletions. A recurrent founder mutation, c.223G>A (p.Val75Met), has been documented in eight independent XLT cases (PMID:15946311).

Functional studies demonstrate that pathogenic WAS variants lead to absent or reduced WASP expression by Western blot and flow cytometry in patient lymphocytes and platelets, correlating with microthrombocytopenia severity (PMID:9713366). Affected cell lines exhibit defective F-actin polymerization and impaired Arp2/3-dependent actin nucleation in vitro (PMID:10480940), consistent with animal and cellular models.

The mechanism of pathogenicity is haploinsufficiency: variants causing truncated or unstable WASP provoke isolated thrombocytopenia (XLT), whereas residual expression of missense mutants yields milder platelet phenotypes. The robust correlation of genotype with WASP protein levels and function underpins reliable molecular diagnosis.

Extensive clinical, genetic, and experimental data establish a Definitive association between WAS and Thrombocytopenia 1. WAS gene testing is recommended in males presenting with congenital microthrombocytopenia to guide early intervention and genetic counseling.

Key Take-home Sentence: Early screening for WAS mutations in males with isolated microthrombocytopenia enables prompt diagnosis, management, and familial risk assessment.

References

• American journal of kidney diseases • 2004 • IgA nephropathy associated with X-linked thrombocytopenia. PMID:14981635
• European journal of haematology • 2005 • Recurrent V75M mutation within the Wiskott-Aldrich syndrome protein: description of a homozygous female patient. PMID:15946311
• The Journal of pathology • 1998 • Defective actin polymerization in EBV-transformed B-cell lines from patients with the Wiskott-Aldrich syndrome. PMID:9713366
• Human molecular genetics • 1995 • WASP gene mutations in Wiskott-Aldrich syndrome and X-linked thrombocytopenia. PMID:8528199
• Nature genetics • 1995 • X-linked thrombocytopenia and Wiskott-Aldrich syndrome are allelic diseases with mutations in the WASP gene. PMID:7795648
• Blood • 2004 • Mutations of the Wiskott-Aldrich Syndrome Protein (WASP): hotspots, effect on transcription, and translation and phenotype/genotype correlation. PMID:15284122
• The Journal of Biological Chemistry • 1999 • Wiskott-Aldrich syndrome protein induces actin clustering without direct binding to Cdc42. PMID:10480940

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