Related Experiment Video
Updated: Aug 6, 2025
07:17
Author Spotlight: Advancing the Detection of Low-Frequency Mutations in Cancer Tissues
Published on: August 23, 2024
1.2K
Human PIK3R1 mutations disrupt lymphocyte differentiation to cause activated PI3Kδ syndrome 2
Tina Nguyen1,2, Anthony Lau1,2, Julia Bier1,2
1Garvan Institute of Medical Research , Darlinghurst, Australia.
The Journal of Experimental Medicine
|March 21, 2023
Summary
Loss-of-function mutations in PIK3R1 cause APDS2, impacting B cell and Tfh cell function differently than APDS1. This study reveals unique cellular defects and signaling alterations in PIK3R1 loss-of-function.
Area of Science:
- Immunology
- Genetics
- Molecular Biology
Background:
- Activated PI3Kδ syndrome 2 (APDS2) arises from PIK3R1 loss-of-function (LOF) mutations, presenting clinically similar to APDS1 caused by PIK3CD gain-of-function (GOF) mutations.
- While PIK3CD GOF effects on immune dysregulation are known, the cellular consequences of PIK3R1 LOF remain less understood.
Purpose of the Study:
- To elucidate the cellular and signaling alterations caused by PIK3R1 LOF mutations.
- To compare the cellular defects in APDS2 with those in APDS1.
Main Methods:
- Utilized a novel CRISPR/Cas9 mouse model.
- Analyzed immune cells from patients with APDS2.
- Investigated signaling pathway alterations.
Main Results:
- Observed shared defects in B cell class switching and Tfh cell function between APDS1 and APDS2.
- Identified unique APDS2 phenotypes: impaired B cell expansion, affinity maturation post-immunization, and reduced pup survival.
- Demonstrated distinct signaling pathway modifications between PIK3R1 LOF and PIK3CD GOF.
Conclusions:
- PIK3R1 LOF causes distinct cellular and signaling defects compared to PIK3CD GOF, despite clinical similarities between APDS2 and APDS1.
- Highlights crucial differences in the molecular etiologies of these two related immune disorders.
Related Concept Videos
01:22PI3K/mTOR/AKT Signaling Pathway
3.8K
The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast, mTORC2 consists of a...
3.8K
01:20The JAK-STAT Signaling Pathway
9.1K
Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as SH2...
9.1K
02:23Abnormal Proliferation
4.6K
Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
4.6K
02:38The Ras Gene
6.3K
The Ras-gene-encoded proteins are regulators of signaling pathways controlling cell proliferation, differentiation, or cell survival. The Ras-gene family in humans constitutes three primary members—the HRas, NRas, and KRas. These genes code for four functionally distinct yet closely related proteins—the HRas, NRas, KRas4A, and KRas4B. The involvement of mutant Ras genes in human cancer was first discovered in 1982 and is among the most common causes of human tumorigenesis.
Ras is a...
Ras is a...
6.3K
01:09Cytoskeletal Linker Proteins - Plakins
2.4K
Plakins are large proteins with binding domains for microtubules, microfilaments, intermediate filaments, and membrane-associated protein complexes at cell junctions. Plakin functions are evolutionarily conserved and are primarily involved in organizing the different components of the cytoskeleton by crosslinking them to each other and connecting them to the cell-matrix and cell adhesion complexes. They are also known to interact with signal transducers, serve as scaffolds for signaling...
2.4K
03:03mTOR Signaling and Cancer Progression
3.8K
The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
The mTOR pathway or the...
3.8K