Mutation hotspots in the PHKA2 gene in X-linked liver glycogenosis due to phosphorylase kinase deficiency with atypical activity in blood cells (XLG2)

In five cases of X-linked liver glycogenosis subtype 2 (XLG2), we haveidentified mutations in the gene encoding the liver isoform of thephosphorylase kinase alpha subunit (PHKA2). XLG2 is a rare variant of X-linked phosphorylase kinase (Phk) deficiency of the liver. Whereas in themore common form of X-linked hepatic Phk deficiency, XLG1, the enzyme'sactivity is decreased both in liver and in blood cells, Phk activity inXLG2 is low in liver but normal or even enhanced in blood cells. Althoughmissense, nonsense and splicesite mutations in the PHKA2 gene were recentlyidentified in several cases of XLG1, no mutations have yet been describedfor XLG2 and a molecular explanation for the peculiar biochemical phenotypeof XLG2 has been lacking. All mutations found in the present study resultin non-conservative amino acid replacements of residues that are absolutelyconserved between the alpha L, alpha M and beta subunits of Phk [H132P,H132Y, R186H (twice) and D299G]. Strikingly, in two pairs of cases themutations affect the same codon. These results demonstrate that: (i) XLG2is caused by mutations in PHKA2 and is therefore allelic with XLG1; and(ii) XLG2 mutations appear to cluster in limited sequence regions or evenindividual codons.