X-linked liver glycogenosis type II (XLG II) is caused by mutations in PHKA2, the gene encoding the liver alpha subunit of phosphorylase kinase

Abstract

X-linked liver glycogenosis type II (XLG II) is a recently described X-linked liver glycogen storage disease, mainly characterized by enlarged liver and growth retardation. These clinical symptoms are very similar to those of XLG I. In contrast to XLG I patients, however, XLG II patients do not show an in vitro enzymatic deficiency of phosphorylase kinase (PHK). Recently, mutations were identified in the gene encoding the liver alpha subunit of PHK (PHKA2) in XLG I patients. We have now studied the PHKA2 gene of four unrelated XLG II patients and identified four different mutations in the open reading frame, including a deletion of three nucleotides, an insertion of six nucleotides and two missense mutations. These results indicate that XLG II is due to mutations in PHKA2. In contrast to XLG I, XLG II is caused by mutations that lead to minor structural abnormalities in the primary structure of the liver alpha subunit of PHK. These mutations are found in a conserved RXX(X)T motif, resembling known phosphorylation sites that might be involved in the regulation of PHK. These findings might explain why the in vitro PHK enzymatic activity is not deficient in XLG II, whereas it is in XLG I.

Clinical application of massively parallel sequencing in the molecular diagnosis of glycogen storage diseases of genetically heterogeneous origin

“…The enzyme PhK activates the inactive form of glycogen phosphorylase b to the active form, phosphorylase a, and the total phosphorylase activity is regulated by PhK. 29 Therefore, a deficiency in glycogen phosphorylase may be the result of impairment of the phosphorylase itself or of its regulatory protein, the glycogen phosphorylase kinase, PhK. Furthermore, there are multiple tissue-specific forms of PhK subunits that may be responsible for the apparent phosphorylase deficiency.…”

Viral infection and human disease - insights from minimotifs

“…X-linked Liver Glycogenosis Type II have a deficiency in Phosphorylase Kinase activity. Several of these mutations cluster around a R 1111 EMT 1114 sequence with a T→I mutation or an insertion after R 1111 ; These mutations eliminate a consensus phosphorylation site for several kinases (76). In patients with Familial Dysautonomia, the IκB kinase complex-associated protein (IKAP) has a R 696 →P mutation in a RxxT consensus sequence for Calmodulin Kinase II phosphorylation (77).…”

Clinical, biochemical and molecular findings in a patient with X-linked liver glycogenosis followed for 40 years

“…This assumption is corroborated by the fact that this region is strongly conserved in the rabbit liver a subunit [3], human [27], mouse [22] and rabbit [28] muscle a subunits, and in the a subunit from Clostridium elegans [23]. Previously, we have proposed that mutations in XLG II might impair the activation of the PHK enzyme, whereas mutations in XLG I might disturb the stability of PHK [13]. In vitro assays may fail todemonstrate the full extent of the de®ciency in XLG II since they only measure the net activity of PHK and not its activation state.…”

“…As it is dicult to classify these patients, many of them probably have been diagnosed incorrectly. Recently, however, also this liver GSD has been shown to be caused by mutations in the PHKA2 gene [1,13,14]. Consequently, this group has been designated XLG II, in contrast to XLG I (patients with a clear-cut enzymatic de®ciency of PHK) [11,21].…”