X-linked liver glycogenosis: localization and isolation of a candidate gene

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Abstract
X-linked phosphorylase kinase (PHK) deficiency causes X-linked liver glycogenosis (XLG) which is the most frequent liver glycogen storage disorder in man. Recently we assigned XLG to the Xp22 chromosomal region by linkage analysis in two families segregating XLG. In this study a further localization of XLG in Xp22 was performed by extending the number of Xp22 markers, by extension of the number of family members from the two families of our previous study and by linkage analysis in four additional XLG families. Two-point linkage analysis revealed led scores of 4.60, 5.73, 5.28, 8.62 and 5.14 for linkage between XLG and the DNA markers pXUT23 and pSE3.2-L(DXS16), pD2(DXS43), pTS247(DXS197) and pPA4B(DXS207), respectively, all at 0% recombination. Linkage heterogeneity was not observed in this set of families. Multipoint linkage analysis increased the led score for linkage between XLG and Xp22 to 16.79 relative to DXS197/DXS207 The position of the XLG gene was confirmed by analysis of recombinational events locating the XLG gene between DXS85 and DXS41. The XLG gene could not be mapped more precisely in this chromosomal region of approximately 20cM because of the absence of recombinatlonal events between the XLG gene and the Xp22 markers. As we have previously shown that the rabbit liver α subunit of PHK (PHKA2) hybridizes to human Xp22, we isolated a human PHKA2 cDNA from a human hepatoma λ gt11 cDNA library. 1 in situ hybridization mapped human PHKA2 to Xp22. As this physical mapping coincidies with the genetic mapping of XLG by linkage analysis, PHKA2 most probably harbours the mutation(s) responsible for XLG.

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