Differential expression of the phosphorylase kinase catalytic subunit gamma 2 in cancers of the breast.

Breast cancer affects women at relatively high frequency (1). We mined published microarray datasets (2, 3) to determine in an unbiased fashion and at the systems level genes most differentially expressed in the primary tumors of patients with breast cancer. We report here significant differential expression of the gene encoding the phosphorylase kinase catalytic subunit gamma 2, PHKG2, when comparing primary tumors of the breast to the tissue of origin, the normal breast. PHKG2 mRNA was present at significantly higher quantities in tumors of the breast as compared to normal breast tissue. Analysis of human survival data revealed that expression of PHKG2 in primary tumors of the breast was correlated with recurrence-free survival in patients with luminal A and luminal B type cancers, demonstrating a relationship between correlation of primary tumor expression with recurrence-free survival based on molecular subtype. PHKG2 may be of relevance to initiation, maintenance or progression of cancers of the female breast.

Variability of clinical and biochemical phenotype in liver phosphorylase kinase deficiency with variants in the phosphorylase kinase (PHKG2) gene

BackgroundPHKG2-related liver phosphorylase kinase deficiency is inherited in autosomal recessive pattern and is a rare type of liver glycogenosis. We demonstrated the clinical presentation and genetic determinants involved in children with PHKG2- related liver phosphorylase kinase deficiency.MethodologyTen Pakistani children with liver phosphorylase kinase from seven different families, were enrolled over a period of 18 months. All regions of the PHKG2 gene spanning exons and splicing sites were evaluated through targeted exome sequencing. Variants were analyzed using different bioinformatics tools. Novel variants were reconfirmed by direct sequencing.ResultsSeven different variants were identified in PHKG2 gene including five novel variants: three stop codons (c.226C>T [p.R76*], c.454C>T [p.R152*] and c.958C>T [p.R320*]), one missense variant c.107C>T (p.S36F) and one splice site variant (c.557-3C>G). All five novel variants were predicted to be damaging by in Silico analysis. The variants are being transmitted through recessive pattern of inheritance except one family (two siblings) has compound heterozygotes. Laboratory data revealed elevated transaminases and triglycerides, normal creatinine phosphokinase and uric acid levels but with glycogen loaded hepatocytes on liver histology.ConclusionPHKG2 related liver phosphorylase kinase deficiency can mimic both liver glycogenosis type I (glucose-6-phosphatase deficiency) & III(amylo-1,6 glucosidase) and characterized by early childhood onset of hepatomegaly, growth restriction, elevated liver enzymes and triglycerides. Molecular analysis would be helpful in accurate diagnosis and proper treatment. The symptoms and biochemical abnormalities in liver glycogenosis due phosphorylase kinase deficiency tend to improve with proper dietary restrictions but need to be monitored for long-term complications such as liver fibrosis and cirrhosis.

Glycogen Storage Disease Type IX due to a Novel Mutation in PHKA2 Gene

We report a case of a 17-month-old male with a history of developmental delay with poor muscle control, hepatomegaly, and transaminitis. Ultrasound of abdomen revealed hepatomegaly with a liver span of 13 cm, homogeneous parenchyma, and normal spleen size. Liver and muscle biopsies were obtained: the liver biopsy revealed distended hepatocytes with excessive glycogen accumulation and fine septate fibrosis. Biopsy of the right vastus lateralis muscle showed focal swollen glycogen containing mitochondria. For the developmental delay, a chromosomal microrarray was ordered. The chromosomal microarray revealed the patient to have 1q21 duplication syndrome and 16p11.2 deletion syndrome. Given the liver and muscle biopsy findings, a glycogen storage disease panel was sent which identified the patient to be hemizygous for a variant of uncertain significance denoted as p.Gly 131Val, c.392G > T in the PHKA2 gene. PKHA2 gene encodes the alpha subunit of hepatic phosphorylase kinase. This change in the PHKA2 gene was in a highly conserved region and had been reported in another patient with decreased enzymatic activity of the phosphorylase kinase and who had symptoms of GSD IX. Based on this, the patient was started on treatment for GSD IX, and his family met with a dietician.

Neurological Involvement in Glycogen Storage Disease Type IXa due to PHKA2 Mutation

ABSTRACT:Glycogen storage diseases (GSDs) result from the deficiency of enzymes involved in glycogen synthesis and breakdown into glucose. Mutations in the gene PHKA2 encoding phosphorylase kinase regulatory subunit alpha 2 have been linked to GSD type IXa. We describe a family with two adult brothers with neonatal hepatosplenomegaly and later onset of hearing loss, cognitive impairment, and cerebellar involvement. Whole-exome sequencing was performed on both subjects and revealed a shared hemizygous missense variant (c.A1561G; p.T521A) in exon 15 of PHKA2. The phenotype broadens the clinical and magnetic resonance imaging spectrum of GSD type IXa to include later onset neurological manifestations.