WIPF1 – Wiskott-Aldrich syndrome

A novel autosomal recessive immunodeficiency due to biallelic loss of WIPF1 has been described in a single female offspring of consanguineous parents presenting with eczematoid dermatitis, thrombocytopenia and recurrent infections consistent with Wiskott-Aldrich syndrome. Genetic analysis revealed a homozygous truncating variant c.1301C>G (p.Ser434Ter) in WIPF1, absence of WASP protein despite normal WAS sequence and mRNA levels, and restoration of WASP expression upon reintroduction of WIP into patient T cells ([PMID:22231303]).

Functional studies further demonstrate that WIP bridges DOCK8 to WASp, and that DOCK8 guanine nucleotide exchange activity is essential for TCR-driven WASp activation, F-actin assembly and immune synapse formation, linking WIPF1 loss to defective actin dynamics in T cells ([PMID:27599296]). These data support a loss-of-function mechanism for WIPF1 in mediating WASp stability and actin cytoskeleton regulation. WIPF1 deficiency should be considered in WAS-like patients with normal WAS gene sequencing. Key Take-home: WIPF1 is a clinically actionable autosomal recessive cause of WAS-like immunodeficiency.

References

• The Journal of experimental medicine • 2012 • A novel primary human immunodeficiency due to deficiency in the WASP-interacting protein WIP. PMID:22231303
• The Journal of clinical investigation • 2016 • A DOCK8-WIP-WASp complex links T cell receptors to the actin cytoskeleton. PMID:27599296

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