Browse views: by Year, by Function, by GLF, by Subfunction, by Conference, by Journal

Pathogenic germline activating mutations in PIK3CD intrinsically compromise B-cell development and function, underlying humoral defects in human primary immunodeficiency

Avery, Danielle A and Kane, Elisa and Nguyen, Tina and Lau, Anthony and Nguyen, Akira and Payne, Kathryn and Lenthall, Ellen and Wei, Shi and Brigden, henry and French , Elise and Bier, Julia and Hermes, Jana R and Zahra, David and Sewell, William and Boztug, Kaan and Meyts, Isabelle and Choo, Sharon and Hsu, Peter and Wong, Melanie and Berglund, Lucinda and Gray, Paul and O'Sullivan, Michael and Cole, Therese and Holland, Steven M and Ma, Cindy S and Burkhart, Christoph and Corcoran, Lynn M and Phan, Tri G and Brink, Robert and Uzel, Gulbu and Deenick, Elissa K and Tanguye, Stuart G (2018) Pathogenic germline activating mutations in PIK3CD intrinsically compromise B-cell development and function, underlying humoral defects in human primary immunodeficiency. Journal of Experimental Medicine.

Abstract

By analysing a large cohort of patients with activating mutations in PIK3CD, and developing a novel mouse model of Pik3cdGOF by CRISPR/Cas9-mediated genome editing, we have now revealed key functions for PI3K in B-cell development and differentiation. B cell development in human BM was perturbed at the pre-BII and immature stages, with an aberrant accumulation of these cells and corresponding reductions in recirculating mature B cells. The study has provided insight into the pathophysiology of PIK3CD GOF mutations. Furthermore, our observations that the Pik3cdE1020K mutation in murine B cells mirrored the effects of PIK3CD GOF mutations in humans underscores the utility of this mouse model to investigate the consequences of hyper-active PI3K signaling, and dissect mechanisms of disease pathogenesis in humans with corresponding mutations. Thus, these mice will be a valuable pre-clinical model to screen new or alternative pharmacological or biological inhibitors or the PI3K pathway as novel therapeutics for humans with PIK3CD GOF mutations.

Item Type: Article
Date Deposited: 01 Aug 2018 00:45
Last Modified: 01 Aug 2018 00:45
URI: https://oak.novartis.com/id/eprint/35042

Search

Email Alerts

Register with OAK to receive email alerts for saved searches.