Variability of biochemical and clinical phenotype in X-linked liver glycogenosis with mutations in the phosphorylase kinase PHKA2 gene
ABSTRACT X-linked liver glycogenosis (XLG) resulting from phosphorylase kinase (Phk) deficiency is one of the most common forms of glycogen storage disease. It is caused by mutations in the gene encoding the liver isoform of the Phk alpha subunit (PHKA2). In the present study, we address the issue of phenotypic and allelic heterogeneity in XLG. We have identified mutations in seven male patients. One of these patients represents the variant biochemical phenotype, XLG subtype 2 (XLG2), where Phk activity is low in liver but normal or even elevated in erythrocytes. He carries a K189E missense mutation, which adds to the emerging evidence that XLG2 is associated with missense mutations clustering at a few sites. Two patients display clinical phenotypes unusual for liver Phk deficiency, with dysfunction of the kidneys (proximal renal tubular acidosis) or of the nervous system (seizures, delayed cognitive and speech abilities, peripheral sensory neuropathy), respectively, in addition to liver glycogenosis. In the patient with kidney involvement, we have identified a missense mutation (P399S) and a trinucleotide deletion (2858del3) leading to the replacement of two amino acids by one new residue (N953/L954I), and a missense mutation has also been found in the patient with neurological symptoms (G1207W). These two cases demonstrate that PHKA2 mutations can also be associated with uncommon clinical phenotypes. Finally, in four typical XLG cases, we have identified three truncating mutations (70insT, R352X, 567del22) and an in-frame deletion of eight well-conserved amino acids (2452del24). Together, this study adds eight new mutations to the previously known complement of sixteen PHKA2 mutations. All known PHKA2 mutations but one are distinct, indicating pronounced allelic heterogeneity of X-linked liver glycogenosis with mutations in the PHKA2 gene.
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- "Phosphorylase kinase, gamma subunit contains a kinase domain and a C-terminal calmodulin binding domain (Hancock and Rice, 2006; Priddy et al., 2007). It has two isoforms encoded by PHKG1 and PHKG2, PHKG1 located at 7p11.2 and PHKG2 located on the 16 chromosome in region 16p11.2-12.1 of human (Jones et al., 1990; Burwinkel et al., 1998a). "
ABSTRACT: Phosphorylase kinase, gamma 2 gene (PHKG2) encodes the catalytic subunit of phosphorylase kinase which is a regulatory enzyme in the cascade activation of glycogenolysis. In order to further understand the functions of the porcine PHKG2 gene, we obtained the complete open reading frame sequences and the determination of its expression by real-time PCR. Our spatial expression analysis showed that porcine PHKG2 gene was highly expressed in spleen, uterus and ovary. In contrast, low levels of expression of this gene were evident in heart, liver, lung, kidney, stomach, small intestine or fat, and much lower levels in skeletal muscle. Three SNPs, 785G>A, 866G>A and 875G>A were identified, their genotypes and allelic frequencies were analyzed. The frequencies of the G allele were dominant in Western pig breeds and the frequencies of the A allele were dominant in Chinese indigenous breeds in all analyzed polymorphisms. Haplotypes harboring these three polymorphisms were examined in five breeds, a total of 8 haplotypes were found in those breeds, which was equal to the theoretically expected number (23). The date presented here provided information about the functions of porcine PHKG2 gene.Livestock Science 05/2009; 122(1):90-93. DOI:10.1016/j.livsci.2008.07.026 · 1.10 Impact Factor
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- "Deficiency of PhK results in glycogen-storage disease (GSD) type IX. It is the most frequent inherited disorder of glycogen metabolism, accounting for approximately 25 % of all cases of GSDs (approximately 1/100,000 births) . Mutations of the liver isoforms of PhK α or γ subunits (PHKA2 and PHKG2 genes) cause liver-specific glycogenoses   . "
ABSTRACT: Mutations in the liver isoform of the Phosphorylase Kinase (PhK) alpha subunit (PHKA2 gene) cause X-linked liver glycogenosis (XLG), the most frequent type of PhK deficiency (glycogen-storage disease type IX). XLG patients can be divided in two subgroups, with similar clinical features but different activity of PhK (decreased in liver and blood cells for XLG-I and low in liver but normal or enhanced in blood cells for XLG-II). Here, we show that the PHKA2 missense mutations and small in-frame deletions/insertions are concentrated into two domains of the protein, which were recently described. In the N-terminal glucoamylase domain, mutations (principally leading to XLG-II) are clustered within the predicted glycoside-binding site, suggesting that they may have a direct impact on a possible hydrolytic activity of the PhK alpha subunit, which remains to be demonstrated. In the C-terminal calcineurin B-like domain (domain D), mutations (principally leading to XLG-I) are clustered in a region predicted to interact with the regulatory region of the PhK catalytic subunit and in a region covering this interaction site. Altogether, these results show that PHKA2 missense mutations or small in-frame deletions/insertions may have a direct impact on the PhK alpha functions and provide a framework for further experimental investigation.Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 11/2008; 1782(11):664-70. DOI:10.1016/j.bbadis.2008.09.011 · 5.09 Impact Factor
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- "Additionally, two previously described XLG II mutations, both of which change the arginine codon at amino acid position 186, were shown to be present in additional patients with XLG II. The R186H mutation (Burwinkel et al. 1996; Hendrickx et al. 1998) was found in patient 7, who belongs to a family of French descent that contains three patients in three generations. This patient was included in an earlier study, by Maire et al. (1991). "
ABSTRACT: X-linked liver glycogenosis (XLG) is probably the most frequent glycogen-storage disease. XLG can be divided into two subtypes: XLG I, with a deficiency in phosphorylase kinase (PHK) activity in peripheral blood cells and liver; 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 mutations in the same gene, PHKA2, that encodes the regulatory alpha subunit of PHK. To facilitate mutation analysis in PHKA2, we determined its genomic structure. The gene consists of 33 exons, spanning >/=65 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 II, bringing the total to 19 XLG I and 12 XLG II mutations. Most XLG I mutations probably lead to truncation or disruption of the PHKA2 protein. In contrast, all XLG II mutations are missense mutations or small in-frame deletions and insertions. These results suggest that the biochemical differences between XLG I and XLG II might 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 mutations may lead to in vivo deregulation of PHK, which might be difficult to demonstrate in vitro.The American Journal of Human Genetics 06/1999; 64(6):1541-9. DOI:10.1086/302399 · 10.99 Impact Factor