| 1996 |
Mutations in PHKG2 (the testis/liver isoform of the phosphorylase kinase catalytic gamma subunit) cause autosomal liver-specific phosphorylase kinase deficiency. Non-conservative amino acid replacements (V106E, G189E, D215N) at highly conserved residues within the catalytic core of the kinase domain, as well as a frameshift mutation, abolish normal function; PHKG2 is identified as the predominant catalytic gamma subunit isoform in liver, erythrocytes, and non-muscle tissues. |
Sequencing of PHKG2 in human patients with autosomal liver glycogenosis and in the gsd rat strain; mutation analysis identifying frameshift and missense mutations in conserved catalytic core residues |
Nature genetics |
High |
8896567
|
| 1997 |
A splice-site mutation (IVS4+1 g→a) in PHKG2 causes skipping of exon 4, resulting in a frameshift starting at nucleotide 272, a premature stop codon after 32 additional amino acids, and subsequent loss of the catalytic site, causing liver phosphorylase kinase deficiency. |
Exon-specific amplification and direct sequencing of PHKG2 genomic DNA; functional inference from loss of catalytic site due to frameshift |
Biochemical and biophysical research communications |
Medium |
9245685
|
| 1998 |
The human PHKG2 gene spans 9.5 kb, is divided into 10 exons, and intron positions are highly conserved with PHKG1 (muscle isoform), indicating conserved gene structure between the two gamma subunit isoforms. Translation-terminating mutations (277delC and Arg44ter) in PHKG2 are associated with progression to liver cirrhosis, suggesting that the severity of PHKG2 loss-of-function correlates with cirrhosis risk. |
Genomic sequencing and gene structure determination; mutation identification in cirrhotic patients |
Human molecular genetics |
Medium |
9384616
|
| 2021 |
Knockout of Phkg2 in mice (Phkg2-/- model) leads to significantly decreased liver phosphorylase kinase enzyme activity, increased liver glycogen accumulation, elevated liver:body weight ratio, elevated serum liver markers, and early liver fibrosis, with no glycogen accumulation in brain, muscle, kidney, or heart — establishing that PHKG2 encodes the liver-specific catalytic subunit of phosphorylase kinase responsible for hepatic glycogen breakdown. |
Targeted gene knockout mouse model; enzyme activity assays, glycogen content measurement, histology (H&E, Masson's Trichrome), serum liver markers, urinary Glc4 biomarker |
Molecular genetics and metabolism |
High |
34083142
|
| 2022 |
Novel PHKG2 mutations F233S and R320DfsX5 each lead to a decrease in key phosphorylase b kinase enzyme activity, as demonstrated by functional experiments in patient-derived samples. |
Functional enzyme activity assay on patient samples with novel PHKG2 mutations |
BMC pediatrics |
Medium |
35549678
|
| 2023 |
PHKG2 promotes RSL3-induced ferroptosis in H. pylori-positive gastric cancer cells by upregulating the lipoxygenase ALOX5 expression, thereby enhancing lipid peroxidation. |
Cell-based overexpression/knockdown experiments in gastric cancer cell lines; measurement of ferroptosis markers and ALOX5 expression |
Archives of biochemistry and biophysics |
Medium |
36948350
|
| 2024 |
NRF2 transcriptionally represses PHKG2; overexpression of PHKG2 promotes ferritinophagy, elevates intracellular iron levels, and induces mitochondrial stress-dependent ferroptosis in NSCLC cells under radiotherapy. Targeting NRF2 upregulates PHKG2 and reverses radiotherapy resistance. |
High-throughput transcriptome sequencing, Lasso regression, in vitro overexpression/knockdown, ferritinophagy and iron level assays, mitochondrial function assays, in situ transplantation tumor models in vivo |
NPJ precision oncology |
Medium |
39169204
|
| 2025 |
TP53 transcriptionally activates PHKG2; PHKG2 phosphorylates PPP1R3B at specific residues, disrupting its interaction with PP1C and thereby enhancing PP1 phosphatase activity; activated PP1 dephosphorylates NRF2, promoting NRF2 nuclear export and suppressing GPX4 transcription, which sensitizes HNSCC cells to ferroptosis. This defines a TP53/PHKG2–PP1–NRF2 signaling axis. |
In vitro and in vivo overexpression experiments; phosphorylation assays demonstrating PHKG2 phosphorylates PPP1R3B (T225, T306); co-immunoprecipitation showing disruption of PPP1R3B–PP1C interaction; NRF2 nuclear export assays; GPX4 transcription assays; lipid peroxidation measurement; xenograft tumor models |
Cell death & disease |
Medium |
40885710
|
| 2026 |
PHKG2 mediates cisplatin resistance in ESCC by phosphorylating IGF2BP3 at residues T225 and T306; this phosphorylation enhances IGF2BP3 phase separation, stabilizing CXCL8 mRNA in an m6A-dependent manner; increased CXCL8 secretion then promotes M2 macrophage polarization and suppresses CD8+ T cell cytotoxicity. Pharmacological inhibition of PHKG2 by prexasertib curtails ESCC proliferation and enhances cisplatin sensitivity. |
CRISPR/Cas9 knockout library functional screening; transcriptomic profiling; in vitro phosphorylation assays identifying IGF2BP3 T225/T306 as PHKG2 substrates; phase separation assays; mRNA stability assays; macrophage polarization assays; in vivo validation; pharmacological inhibition with prexasertib |
Cell death & disease |
Medium |
42161921
|
| 2025 |
A deep intronic variant in PHKG2 causes aberrant splicing (confirmed by short-read and long-read RNA-seq in patient blood and a CRISPR-edited HEK293T cell model), leading to PHKG2 deficiency consistent with GSD IX γ2. Antisense splice-switching oligonucleotides reverse the aberrant splicing in the cell model, demonstrating the causal role of this non-coding variant in PHKG2 dysfunction. |
Whole genome sequencing; short-read and long-read RNA-seq on patient blood; CRISPR-installed variant in HEK293T cells; antisense oligonucleotide rescue experiments |
bioRxivpreprint |
Medium |
bio_10.1101_2025.05.14.654043
|