Details

Autor(en) / Beteiligte

• Hsu, Amy P

Titel

Not too little, not too much: the impact of mutation types in Wiskott-Aldrich syndrome and RAC2 patients

Ist Teil von

• Clinical and experimental immunology, 2023-04, Vol.212 (2), p.137-146

Ort / Verlag

US: Oxford University Press

Erscheinungsjahr

2023

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• Abstract Primary immune deficiencies (PIDs) are genetic disorders impacting the appropriate development or functioning of any portion of the immune system. The broad adoption of high-throughput sequencing has driven discovery of new genes as well as expanded phenotypes associated with known genes. Beginning with the identification of WAS mutations in patients with severe Wiskott-Aldrich Syndrome, recognition of WAS mutations in additional patients has revealed phenotypes including isolated thrombocytopenia and X-linked neutropenia. Likewise RAC2 patients present with vastly different phenotypes depending on the mutation–ranging from reticular dysgenesis or severe neutrophil dysfunction with neonatal presentation to later onset common variable immune deficiency. This review examines genotype-phenotype correlations in patients with WAS (Wiskott-Aldrich Syndrome) and RAC2 mutations, highlighting functional protein domains, how mutations alter protein interactions, and how specific mutations can affect isolated functions of the protein leading to disparate phenotypes. Both gain- and loss-of-function mutations in Wiskott-Aldrich syndrome (WAS) and RAC2 are found throughout the genes and cause immunodeficiencies involving leukocyte actin remodeling. Patient phenotypes differ based on gain or loss of protein function or loss of protein. Identified RAC2 mutations include dominant loss-of-function resulting in severe infantile onset disease similar to leukocyte adhesion deficiency (LAD-like LOF) in which RAC2 cannot activate downstream effectors (black), dominant gain-of-function causing severe combined immune deficiency (SCID GOF) with constitutively activate RAC2 (bold red), and prolonged activated RAC2 causing common variable immune deficiency (CVID GOF) in which RAC2 fails to rapidly hydrolyze GTP but maintains intrinsic hydrolysis (salmon). Graphical Abstract Both gain- and loss-of-function mutations in Wiskott-Aldrich syndrome (WAS) and RAC2 are found throughout the genes, causing immunodeficiencies involving leukocyte actin remodeling. Patient phenotypes differ based on gain or loss of protein function or loss of protein. This review highlights the correlation between WAS and RAC2 mutations and patient presentations and explores the expanding cellular roles recognized for the two proteins.