Mutations in the testis/liver isoform of the phosphorylase kinase γ subunit (PHKG2) cause autosomal liver glycogenosis in the gsd rat and in humans

@article{Maichele1996MutationsIT,
  title={Mutations in the testis/liver isoform of the phosphorylase kinase $\gamma$ subunit (PHKG2) cause autosomal liver glycogenosis in the gsd rat and in humans},
  author={Andrea J. Maichele and Barbara Burwinkel and Irène Maire and Oddmund S{\o}vik and Manfred W Kilimann},
  journal={Nature Genetics},
  year={1996},
  volume={14},
  pages={337-340}
}
Heritable deficiency of phosphorylase kinase (Phk), a regulatory enzyme of glycogen metabolism, is responsible for 25% of all cases of glycogen storage disease and occurs with a frequency of ∼1 in 100,000 births. It is genetically and clinically heterogeneous, occurring in X-linked and autosomal-recessive forms and exhibiting various patterns of principally affected tissues (liver only, muscle only, liver and muscle, liver and kidney, heart only)1. This heterogeneity is thought to reflect the… 

Liver glycogenosis due to phosphorylase kinase deficiency: PHKG2 gene structure and mutations associated with cirrhosis.

TLDR
Employing the gene sequence, homozygous translation-terminating mutations, 277delC and Arg44ter, are identified in the two published cases of liver Phk deficiency who developed cirrhosis in childhood, suggesting that PHKG2 mutations are associated with an increased Cirrhosis risk.

Autosomal glycogenosis of liver and muscle due to phosphorylase kinase deficiency is caused by mutations in the phosphorylase kinase beta subunit (PHKB).

TLDR
Severe translation-disrupting mutations occur in constitutively expressed sequences of the only known beta subunit gene of phosphorylase kinase, PHKB, and are associated with a surprisingly mild clinical phenotype, affecting virtually only the liver, and relatively high residual enzyme activity of approximately 10%.

Phosphorylase-kinase-deficient liver glycogenosis with an unusual biochemical phenotype in blood cells associated with a missense mutation in the β subunit gene (PHKB)

TLDR
The present case demonstrates that mutations in Phk genes other than PHKA2 can also be associated with untypically high activity in certain blood cell types and emphasizes that missense mutations inPhk may cause unusual patterns of tissue involvement that would not be predicted a priori from the tissue specificity of expression of the mutated gene sequences.

A mutation in GLUT2, not in phosphorylase kinase subunits, in hepato-renal glycogenosis with Fanconi syndrome and low phosphorylase kinase activity.

TLDR
Findings indicate that there is no specific subtype of genetic Phk deficiency giving rise to hepato-renal glycogenosis and provide further evidence that Fanconi-Bickel syndrome is caused by GLUT2 mutations.

A mutation in GLUT2, not in phosphorylase kinase subunits, in hepato-renal glycogenosis with Fanconi syndrome and low phosphorylase kinase activity

TLDR
Findings indicate that there is no specific subtype of genetic Phk deficiency giving rise to hepato-renal glycogenosis and provide further evidence that Fanconi-Bickel syndrome is caused by GLUT2 mutations.

Autosomal recessive phosphorylase kinase deficiency in liver, caused by mutations in the gene encoding the beta subunit (PHKB).

TLDR
It is concluded that the deficiency of phosphorylase kinase in this proband is caused by compound heterozygosity for the 1827G-->A and the IVS30(-1),g-->t mutations and that the 2309A-->G mutation is a polymorphism.

A Mouse Model of Glycogen Storage Disease Type IX-Beta: A Role for Phkb in Glycogenolysis

TLDR
Metabolic and molecular analysis confirmed that Phkb−/− mice were capable of sustaining energy homeostasis during prolonged fasting by using partial glycogenolysis, increased gluconeogenesis, and potentially fatty acid oxidation in the liver.

Autosomal recessive liver phosphorylase kinase deficiency caused by a novel splice-site mutation in the gene encoding the liver gamma subunit (PHKG2).

TLDR
It is concluded that deficiency of phosphorylase kinase in liver of the patients is caused by the IVS4 + 1(g --> a) mutation, which is associated with development of liver fibrosis.

Variability of biochemical and clinical phenotype in X-linked liver glycogenosis with mutations in the phosphorylase kinase PHKA2 gene

TLDR
This study adds eight new mutations to the previously known complement of sixteen PHKA2 mutations, indicating pronounced allelic heterogeneity of X-linked liver glycogenosis with mutations in thePHKA2 gene.
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References

SHOWING 1-10 OF 32 REFERENCES

REPORTS Human muscle glycogenosis due to phosphorylase kinase deficiency associated with a nonsense mutation in the muscle isoform of the α subunit

TLDR
The condition of this patient is a human homolog of the X-linked muscle Phk deficiency of I-strain mice, and the first description of a human PhK deficiency mutation is described, to the authors' knowledge.

cDNA cloning of a liver isoform of the phosphorylase kinase alpha subunit and mapping of the gene to Xp22.2-p22.1, the region of human X-linked liver glycogenosis.

TLDR
Sequence comparison with the previously characterized muscle isoform reveals a pattern of highly conserved and variable domains and demonstrates that the isoforms are the products of distinct genes.

Mutation hotspots in the PHKA2 gene in X-linked liver glycogenosis due to phosphorylase kinase deficiency with atypical activity in blood cells (XLG2).

TLDR
X-linked liver glycogenosis subtype 2 (XLG2) is caused by mutations in PHKA2 and is therefore allelic with XLG1; and XLG2 mutations appear to cluster in limited sequence regions or even individual codons.

Assignment of human genes for phosphorylase kinase subunits alpha (PHKA) to Xq12-q13 and beta (PHKB) to 16q12-q13.

TLDR
Southern blot analysis of rodent x human somatic cell hybrid panels, as well as in situ chromosomal hybridization, have provided evidence of single sites for both genes, consistent with the proximity of the Phk and Pgk-1 loci on the mouse X chromosome.

The Testis Isoform of the Phosphorylase Kinase Catalytic Subunit (PhK-T) Plays a Critical Role in Regulation of Glycogen Mobilization in Developing Lung (*)

TLDR
The results suggest that PhK-T plays a critical role in mobilization of glycogen during fetal lung development and that failure to catabolize glycogen in the gsd/gsd rat is related to an untranslatable Phk-T RNA or unstable protein.

Messenger ribonucleic acid encoding an apparent isoform of phosphorylase kinase catalytic subunit is abundant in the adult testis.

  • S. Hanks
  • Biology
    Molecular endocrinology
  • 1989
TLDR
From a cross-species Northern hybridization experiment using adult rat tissue RNA, a transcript homologous to PSK-C3 was found to be abundant in the testis but could not be detected in any of 12 other tissues tested, including skeletal muscle, liver, and ovary.

X-linked liver glycogenosis type II (XLG II) is caused by mutations in PHKA2, the gene encoding the liver alpha subunit of phosphorylase kinase.

TLDR
Results indicate that XLG II is due to mutations in PHKA2, and these mutations are found in a conserved RXX(X)T motif, resembling known phosphorylation sites that might be involved in the regulation of PHK.