Complete genomic structure and mutational spectrum of PHKA2 in patients with X-linked liver glycogenosis type I and II

X-linked liver glycogenosis (XLG) is probably the most frequent glycogen-st orage disease. XLG can be divided into two subtypes: XLG I, with a deficien cy in phosphorylase kinase (PHK) activity in peripheral blood cells and liv er; and XLG II, with normal in vitro PHK activity in peripheral blood cells and with variable activity in liver. Both types of XLG are caused by mutat ions in the same gene, PHKA2, that encodes the regulatory alpha subunit of PHK. To facilitate mutation analysis in PHKA2, we determined its genomic st ructure. The gene consists of 33 exons, spanning greater than or equal to 6 5 kb. By SSCP analysis of the different PHKA2 exons, we identified five new XLG I mutations, one new XLG II mutation, and one mutation present in both a patient with XLG I and a patient with XLG IT, bringing the total to 19 X LG I and 12 XLG II mutations. Most XLG I mutations probably lead to truncat ion or disruption of the PHKA2 protein. In contrast, all XLG II mutations a re missense mutations or small in-frame deletions and insertions. These res ults suggest that the biochemical differences between XLG I and XLG TT migh t be due to the different nature of the disease-causing mutations in PHKA2. XLG I mutations may lead to absence of the alpha subunit, which causes an unstable PHK holoenzyme and deficient enzyme activity, whereas XLG II mutat ions may lead to in vivo deregulation of PHK, which might be difficult to d emonstrate in vitro.