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

Abstract

Glycogen storage disease due to phosphorylase kinase deficiency occurs in several variants that differ in mode of inheritance and tissue-specificity. This heterogeneity is suspected to be largely due to mutations affecting different subunits and isoforms of phosphorylase kinase. The gene of the ubiquitously expressed beta subunit, PHKB, was a candidate for involvement in autosomally transmitted phosphorylase kinase deficiency of liver and muscle. To identify such mutations, the complete PHKB coding sequence was amplified by RT-PCR of RNA isolated from blood samples of patients and analyzed by direct sequencing of PCR products. The characterization of mutations was complemented by PCR of genomic DNA. In one female and four male patients, we identified five independent nonsense mutations (Y418ter; R428ter; Y974H+E975ter; Q656ter in two cases), one single-base insertion in codon N421, one splice-site mutation affecting exon 31, and a large deletion involving the loss of exon 8. Although these severe translation-disrupting mutations occur in constitutively expressed sequences of the only known beta subunit gene of phosphorylase kinase, PHKB, they are associated with a surprisingly mild clinical phenotype, affecting virtually only the liver, and relatively high residual enzyme activity of approximately 10%.

Muscle glycogenosis with low phosphorylase kinase activity: mutations in PHKA1, PHKG1 or six other candidate genes explain only a minority of cases

“…Similarity with the a subunits in this sequence region is low, but the RLQT motif of which glutamine 657 is part may correspond to an RIQT/RVQL motif present in a colinear position in the a M and a L subunits, respectively. The same PHKB nucleotide residue has been found mutated in two unrelated patients with liver Phk deficiency (there, however, to a T residue creating a stop codon), 7 suggesting that it may be hypermutable. Neither of these two single-nucleotide replacements was found in 52 additional PHKB chromosomes that we have analysed to date by sequencing.…”

“…The amplified interval extended between nucleotides -12 and 3377 (including primers) in six overlapping segments. 7 RT-PCR products from muscle included the muscle-specific exon 26 whereas RT-PCR products from blood contained the nonmuscle exon 27 and additionally exon 2, as is known from normal controls. 31 In the latter cases, exon 26 and its surrounding intron sequences (À197 to +124) were amplified from genomic DNA.…”

“…4 -6 Mutations in the ubiquitously expressed exons of the b subunit (PHKB) cause Phk deficiency in liver and muscle, though primarily the liver is clinically affected. 7,8 Liver Phk deficiency manifests in infancy or childhood with hepatomegaly and growth retardation. It is generally a benign condition whose clinical features often remit as the patients grow up.…”

Fatal Infantile Cardiac Glycogenosis with Phosphorylase Kinase Deficiency and a Mutation in the γ2-Subunit of AMP-Activated Protein Kinase

“…The most common cause of neonatal cardiac glycogenosis, Pompe disease, was unlikely on clinical grounds (infants with Pompe disease are floppy, have hepatomegaly and often macroglossia) and was excluded PHK deficiency has been associated with five main syndromes distinguished by inheritance and by tissue involvement: (i) a benign X-linked recessive liver disease of infancy or childhood (14); (ii) an autosomal recessive liver and muscle disease (15); (iii) a pure myopathy affecting both sexes but predominantly men (16); (iv) an autosomal recessive severe liver disease associated with cirrhosis (17) and (v) the fetal infantile cardiopathy described here.…”

Genetic Disorders Leading to Hypoglycaemia

“…Both GSD IXb and c forms present with hepatomegaly, hypoglycaemia, liver dysfunction, fasting ketosis and hypotonia [41,47]. GSD IXb and c are AR inherited and is caused by mutation in the PHKB and PHKG2 genes encoding phosphorylase kinase on chromosome 16 [48,49].…”