Alternative titles; symbols
HGNC Approved Gene Symbol: PYGL
SNOMEDCT: 29291001; ICD10CM: E74.09;
Cytogenetic location: 14q22.1 Genomic coordinates (GRCh38) : 14:50,905,217-50,944,483 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 14q22.1 | Glycogen storage disease VI | 232700 | Autosomal recessive | 3 |
Phosphorylases (EC 2.4.1.1), such as PYGL, remove glycosyl units from the terminal branches of glycogen through phosphorolysis, forming glucose 1-phosphate. During stress, exercise, hypoxia, and hypoglycemia, phosphorylase activity is primarily regulated by interconversion of the active phosphorylated form and the inactive, nonphosphorylated form (summary by Ercan-Fang et al., 2002).
Newgard et al. (1986) reported the cDNA sequence encoding human liver glycogen phosphorylase. The deduced protein contains 845 amino acids.
Burwinkel et al. (1998) reported corrections in the previously reported PYGL coding sequence and polymorphisms in that sequence.
Burwinkel et al. (1998) reported a partial PYGL gene structure showing introns in the same positions as in PYGM (608455), which encodes the muscle isoform of phosphorylase.
By the method of chromosome sorting and spot blotting, Newgard et al. (1987) assigned the structural gene for hepatic phosphorylase to chromosome 14. The gene in the mouse maps to chromosome 12 (Glaser et al., 1989).
Gross (2011) mapped the PYGL gene to chromosome 14q22.1 based on an alignment of the PYGL sequence (GenBank AF046785) with the genomic sequence (GRCh37).
Using recombinant proteins expressed in insect cells, Ercan-Fang et al. (2002) measured the effects of small molecular mass molecules on the phosphorylase activities of the rat and human LGP active forms (LGPa). When added individually at estimated physiologic concentrations, AMP stimulated, whereas ADP, ATP, and glucose inhibited, both enzymes. However, glucose inhibition was about 2-fold more potent with the human enzyme. UDP-glucose, glucose 6-phosphate, and fructose 1-phosphate were only minor inhibitors of both enzymes. When all effectors were present in combination at estimated intracellular concentrations, the net effect reduced human LGPa activity, but it had little effect on rat Lgpa activity. This inhibition of human LGPa was glucose dependent. Ercan-Fang et al. (2002) concluded that glucose may be a major regulator of human LGPa activity, since glucose concentration changes greatly with feeding and fasting.
In 3 patients with glycogen storage disease VI (GSD6; 232700), also known as Hers disease, Burwinkel et al. (1998) identified mutations in the PYGL gene in homozygous or compound heterozygous state (613741.0001-613741.0004).
By sequencing genomic DNA in a Mennonite family segregating glycogen storage disease VI, Chang et al. (1998) identified a homozygous abnormality of the intron 13 splice donor (613741.0005). This mutation was estimated to be present on 3% of Mennonite chromosomes.
Roscher et al. (2014) reported 4 novel mutations in the PYGL gene resulting in GSD VI.
Newgard et al. (1986) compared the human liver phosphorylase cDNA sequence with the previously determined rabbit muscle phosphorylase sequence. Despite an amino acid identity of 80%, the 2 cDNAs exhibited a remarkable divergence in G+C content. In the sequence for muscle phosphorylase, 86% of the nucleotides at the third codon position are either deoxyguanosine or deoxycytidine residues whereas in the liver homolog the figure is only 60%. The liver phosphorylase cDNA appeared to represent an evolutionary mosaic; the segment encoding the N-terminal 80 amino acids contained more than 90% G+C at the third codon position. Newgard et al. (1986) proposed that the high G+C content in the N-terminal region of the liver message indicates that this segment was spliced onto the liver gene from the muscle gene long after the divergence of liver and muscle tissues. This appears to be evidence for exon shuffling as proposed by Gilbert (1978). Newgard et al. (1986) considered it of interest, however, that organisms such as the thermophilic bacteria and the protozoan Leischmania, which are exposed to environmental stresses of high temperature and low pH, respectively, have high G+C content in their coding sequences, presumably because the greatest stability of G-C basepairs aids the processes of gene replication, transcription, and, to a lesser extent, translation. Possibly skeletal muscle, which undergoes a fall in pH and a rise in temperature during exercise, represents a similarly stressful environment that selectively maintains high G+C content in expressed genes.
In a 4.5-year-old boy with glycogen storage disease VI (GSD6; 232700), the son of first-cousin Israeli-Arab Bedouin parents, Burwinkel et al. (1998) described a splice site mutation. The patient presented at 2 years of age with hepatomegaly and growth retardation, but had no clinical history of fasting hypoglycemia. He was found to be homozygous for an insertion of 119 nucleotides in codon R589, resulting in a frameshift and introducing a stop codon after 5 missense codons. Sequencing showed that the insert was an intron, presumably intron 14, but with a G-to-A replacement in the GT consensus dinucleotide of the 5-prime splice site. This splice site mutation thus led to the retention of intron 14 and 2 aberrant splice products employing neighboring GT dinucleotides in exon 14 and in intron 14, respectively, as illegitimate 5-prime splice sites. Both parents were heterozygous for the mutation.
In a boy with glycogen storage disease VI (GSD6; 232700), the son of unrelated and healthy parents of Suriname Hindustani background, Burwinkel et al. (1998) identified a splice site mutation in the PYGL gene. The patient presented at age 2 years with hepatomegaly and severe growth retardation. Transaminases were intermittently elevated. Marked glycogen storage in hepatocytes was demonstrated. There was no known parental consanguinity. The child was found to be heterozygous for a G-to-C substitution in the AG consensus of the 3-prime splice site of intron 4 of the PYGL gene. Two missense mutations, val221 to ile (V221I) and asn338 to ser (N338S), were found on the other allele. Burwinkel et al. (1998) thought that the N338S mutation was probably the second disease mutation because codon N338 is absolutely conserved in all 3 isoforms of glycogen phosphorylase and also conserved in plants, yeast, and bacterial phosphorylases; the same cannot be said for the V221.
See 613741.0002 and Burwinkel et al. (1998).
In a girl with glycogen storage disease VI (GSD6; 232700), the daughter of consanguineous Turkish parents, Burwinkel et al. (1998) found homozygosity for an asn376-to-lys missense (N376K) mutation in the PYGL gene. The patient presented with hepatomegaly at the age of 1 year. Body length was at the fiftieth percentile, but weight was at the tenth percentile. Transaminases, triglycerides, and cholesterol were elevated. There was a heavy accumulation of glycogen in the liver.
In affected members of a Mennonite kindred with an autosomal recessive form of glycogen storage disease (GSD6; 232700), Chang et al. (1998) found that the consensus GT at the splice donor site of intron 13 was converted to AT in the PYGL gene. This mutation predicts a PYGL protein with a deletion of either 3 or 34 amino acids.
Burwinkel, B., Bakker, H. D., Herschkovitz, E., Moses, S. W., Shin, Y. S., Kilimann, M. W. Mutations in the liver glycogen phosphorylase gene (PYGL) underlying glycogenosis type VI (Hers disease). Am. J. Hum. Genet. 62: 785-791, 1998. [PubMed: 9529348] [Full Text: https://doi.org/10.1086/301790]
Chang, S., Rosenberg, M. J., Morton, H., Francomano, C. A., Biesecker, L. G. Identification of a mutation in liver glycogen phosphorylase in glycogen storage disease type VI. Hum. Molec. Genet. 7: 865-870, 1998. [PubMed: 9536091] [Full Text: https://doi.org/10.1093/hmg/7.5.865]
Ercan-Fang, N., Gannon, M. C., Rath, V. L., Treadway, J. L., Taylor, M. R., Nuttall, F. Q. Integrated effects of multiple modulators on human liver glycogen phosphorylase alpha. Am. J. Physiol. Endocr. Metab. 283: E29-E37, 2002. [PubMed: 12067839] [Full Text: https://doi.org/10.1152/ajpendo.00425.2001]
Gilbert, W. Why genes in pieces? Nature 271: 501 only, 1978. [PubMed: 622185] [Full Text: https://doi.org/10.1038/271501a0]
Glaser, T., Matthews, K. E., Hudson, J. W., Seth, P., Housman, D. E., Crerar, M. M. Localization of the muscle, liver and brain glycogen phosphorylase genes on linkage maps of mouse chromosomes 19, 12 and 2, respectively. Genomics 5: 510-521, 1989. [PubMed: 2575583] [Full Text: https://doi.org/10.1016/0888-7543(89)90017-7]
Gross, M. B. Personal Communication. Baltimore, Md. 5/20/2011.
Newgard, C. B., Fletterick, R. J., Anderson, L. A., Lebo, R. V. The polymorphic locus for glycogen storage disease VI (liver glycogen phosphorylase) maps to chromosome 14. Am. J. Hum. Genet. 40: 351-364, 1987. [PubMed: 2883891]
Newgard, C. B., Nakano, K., Hwang, P. K., Fletterick, R. J. Sequence analysis of the cDNA encoding human liver glycogen phosphorylase reveals tissue-specific codon usage. Proc. Nat. Acad. Sci. 83: 8132-8136, 1986. [PubMed: 2877458] [Full Text: https://doi.org/10.1073/pnas.83.21.8132]
Roscher, A., Patel, J., Hewson, S., Nagy, L., Feigenbaum, A., Kronick, J., Raiman, J., Schulze, A., Siriwardena, K., Mercimek-Mahmutoglu, S. The natural history of glycogen storage disease types VI and IX: long-term outcome from the largest metabolic center in Canada. Molec. Genet. Metab. 113: 171-176, 2014. [PubMed: 25266922] [Full Text: https://doi.org/10.1016/j.ymgme.2014.09.005]