The Molecular Basis of Skeletal Muscle Phosphorylase Kinase Deficiency

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Abstract
The molecular basis of phosphorylase kinase deficiency was investigated in ICR/IAn mice, which show < 0.2% of normal activity in skeletal muscle (Cohen, P. T. W. and Cohen, P., 1973). The genetics of the deficiency indicate it is a single gene defect on the X‐chromosome (Lyon, J. B., 1970). Phosphorylase kinase was purified from skeletal muscle of a control strain, C 3 H/He‐mg, by three different procedures. (a) Ammonium sulphate precipitation and gel filtration on Sepharose 4B. (b) Hydrophobic chromatography and affinity chromatography on Sepharose 4B to which antibody to rabbit muscle phosphorylase kinase has been linked covalently. (c) Precipitation from muscle extracts with anti‐phosphorylase kinase antibody. All three procedures showed C 3 H/He‐mg phosphorylase kinases were similar to the rabbit muscle enzymes, the structures of the two isoenzyrnes being (αβ?)4 and (α'βγ)4 respectively. The proportion of the (α′βγ)4 isoenzyme relative to the (αβγ)4 isoenzyme was however about 1:1 in murine muscle compared to about 1:10 in rabbit muscle. Since the α and α′ subunits appear to be distinct gene products, the defect in ICR/IAn mice cannot be caused by a mutation in the genes coding for either the α or α′ chains, or 50% of normal activity would be observed. All three procedures for C3H/He‐mg mice failed to detect any of the four subunits α, α′, β and γ in ICR/IAn mice, suggesting that all four chains are absent in the deficiency. An allele for the β‐subunit was identified in rabbits, and the inheritance of the allele showed that it was determined by an autosomal gene. Assuming conservation of X‐linkage between mammals, the defect in ICR/lAn mice cannot be caused by a mutation in a β‐subunit gene. It is proposed that ICR/IAn mice are defective in a control gene located on the X‐chromosome which is required for the expression of structural genes, at least one of which, the gene for the β‐subunit, is located on an autosome. The results imply that interchromosomal transfer of information takes place during the synthesis of phosphorylase kinase.