AUTOSOMAL RECESSIVE PHOSPHORYLASE-KINASE DEFICIENCY IN LIVER, CAUSED BY MUTATIONS IN THE GENE ENCODING THE BETA-SUBUNIT (PHKB)

The association of autosomal recessive phosphorylase kinase deficiency in liver of a 3 1/2-year-old female child with mutations in the gene encoding the common part of the beta subunit of phosphorylase kinase i s reported. The proband had a severe deficiency of phosphorylase kinas e in liver, while the phosphorylase kinase activity in erythrocytes wa s only slightly diminished. She had no symptoms of muscle involvement. The complete coding sequences of the liver gamma subunit and of the b eta subunit of phosphorylase kinase of the proband were analyzed for t he presence of mutations, by either reverse-transcribed PCR or SSCP an alysis. Three deviations from the normal sequence were found in the re gion encoding the common part of the beta subunit of phosphorylase kin ase-namely, a 1827G-->A (W609X) transition, a 2309A-->G (Y770C) transi tion, and a deletion of nucleotides 2896-2911-whereas no mutations wer e detected in the sequence encoding the liver gamma subunit of phospho rylase kinase. The 1827G-->A mutation and the deletion both result in the formation of early stop codons. Investigation of DNA showed that t he deletion is caused by a splice-acceptor site mutation (IVS30(-1),g- ->t). Family analysis revealed that the 1827G-->A and IVS30(-1),g-->t substitutions are located on different parental chromosomes and that c ompound heterozygosity for these mutations segregates with the disease . The 2309A-->G mutation was detected in 2%-3% of the normal populatio n. Thus, it is concluded that the deficiency of phosphorylase kinase i n 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. This implies that a defect in the sequence encoding the common part of the beta subunit of phosphorylase kinase may present a s liver phosphorylase kinase deficiency.