The phosphorylase B kinase enzyme is a polymer made up of 16 subunits; 4 each of the alpha, beta, gamma and delta subunits. The alpha and beta subunits have regulatory functions, the gamma subunit contains the active site and the delta subunit is calmodulin. It is a serine phosphorylase found primarily in the liver and muscles. The enzyme is responsible for converting glycogen phosphorylase B into its active form of glycogen phosphorylase A. By carrying out its function, it plays an important role in glycogenosis, the glycogen metabolism pathway that releases glucose to cells. The PHKA1 gene encodes the alpha subunit of the muscle-specific phosphorylase B kinase.
Mutations in the PHKA1 gene create a non-functioning phosphorylase kinase enzyme and lead to the accumulation of glycogen in muscle cells. This results in Glycogen Storage Disease, Type IXd (GSD9D), a condition characterized by exercise-induced muscle stiffness and pain.
The gene is located on the long arm of the X chromosome. It spans a length of 135.5 kb of DNA and its coding sequence is spread across 32 exons. The gene encodes a 137.3 kDa protein product comprised of 1223 amino acids. Additional isoforms of the PHKA1 protein exist due to alternatively spliced transcript variants. Around 7 PHKA1 mutations, including deletions and missense, nonsense and splice site variants, have been identified in GSD9D.
Monies et al. (2017) investigated the findings of 1000 diagnostic panels and exomes carried out at a next generation sequencing lab in Saudi Arabia. One male patient suffered from dystonic posturing of the upper limbs, spasticity of the lower limbs, failure to thrive, learning disability and leukoencephalopathy. He also reported a family history of this phenotype. Using whole exome sequencing, a homozygous mutation (c.1174C>T, p.R392X) was identified in exon 12 of the patient’s PHKA1 gene, associated with GSD9D. Given the atypical presentation of the patient, this case helped in the phenotypic expansion of the disorder.
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