title: High frequency of missense mutations in glycogen storage disease type VI.
abstract: Deficiency of liver glycogen phosphorylase in glycogen storage disease (GSD) type VI results in a reduced ability to mobilize glucose from glycogen. Six mutations of the PYGL gene, which encodes the liver isoform of the enzyme, have been identified in the literature. We have characterized eight patients from seven families with GSD type VI and identified 11 novel PYGL gene defects. The majority of the mutations were missense, resulting in the substitution of highly conserved residues. These could be grouped into those that were predicted to affect substrate binding (p.V456M, p.E673K, p.S675L, p.S675T), pyridoxal phosphate binding (p.R491C, p.K681T), or activation of glycogen phosphorylase (p.Q13P) or that had an unknown effect (p.N632I and p.D634H). Two mutations were predicted to result in null alleles, p.R399X and [c.1964_1969inv6;c.1969+1_+4delGTAC]. Only 7 of the 23 (30%) reported PYGL alleles carry nonsense, splice site or frameshift mutations compared to 68-80% of affected alleles of the highly homologous muscle glycogen phosphorylase gene, PYGM, that underlie McArdle disease. There was heterogeneity in the clinical symptoms observed in affected individuals. These varied from hepatomegaly and subclinical hypoglycaemia, to severe hepatomegaly with recurrent severe hypoglycaemia and postprandial lactic acidosis. We conclude that deficiency of liver glycogen phosphorylase is predominantly the result of missense mutations affecting enzyme activity. There are no common mutations and the severity of clinical symptoms varies significantly.
authors: Academic Unit of Child Health, University of Sheffield, Stephenson Wing, Sheffield Children's NHS Trust, Western Bank, Sheffield, S10 2TH, UK. n.j.beauchamp@sheffield.ac.uk
authors: N J
authors: NJ
authors: Beauchamp
authors: J
authors: J
authors: Taybert
authors: M P
authors: MP
authors: Champion
authors: V
authors: V
authors: Layet
authors: P
authors: P
authors: Heinz-Erian
authors: A
authors: A
authors: Dalton
authors: M S
authors: MS
authors: Tanner
authors: E
authors: E
authors: Pronicka
authors: M J
authors: MJ
authors: Sharrard
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005091:Exons; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D025001:Glycogen Phosphorylase, Liver Form / Q000737:chemistry / Q000172:deficiency / Q000235:genetics*; D006011:Glycogen Storage Disease Type IV / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D007223:Infant; D007438:Introns; D019344:Lactic Acid / Q000097:blood; D008099:Liver / Q000201:enzymology*; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D011487:Protein Conformation; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D012720:Severity of Illness Index
chemical_list: D001786:Blood Glucose; D019344:Lactic Acid; D025001:Glycogen Phosphorylase, Liver Form
references: Biochemistry. 1999 Jul 27;38(30):9562-9
references: 10423233
references: Am J Hum Genet. 1998 Apr;62(4):785-91
references: 9529348
references: J Mol Evol. 1997 Jul;45(1):50-9
references: 9211734
references: Mol Cell. 2000 Jul;6(1):139-48
references: 10949035
references: Biochemistry (Mosc). 2002 Oct;67(10):1197-202
references: 12460118
references: J Mol Biol. 1993 Dec 5;234(3):700-21
references: 8254668
references: Hum Mutat. 2006 Jul;27(7):718
references: 16786513
references: J Comput Biol. 1997 Fall;4(3):311-23
references: 9278062
references: Ann Neurol. 2001 Nov;50(5):574-81
references: 11706962
references: Mol Genet Metab. 2003 Jun;79(2):142-5
references: 12809646
references: Hum Mol Genet. 1998 May;7(5):865-70
references: 9536091
references: J Biol Chem. 1988 Mar 15;263(8):3850-7
references: 3346228
references: Nature. 1989 Aug 24;340(6235):609-16
references: 2770867
references: Proc Natl Acad Sci U S A. 1979 Jun;76(6):2886-9
references: 88735
references: EMBO J. 1997 Nov 17;16(22):6646-58
references: 9362479
references: Am J Hum Genet. 1987 Apr;40(4):351-64
references: 2883891
references: Biochemistry. 1987 Dec 15;26(25):8381-9
references: 3126802
references: J Mol Biol. 2002 Sep 13;322(2):413-23
references: 12217700
references: Biochemistry. 1990 Oct 23;29(42):9956-62
references: 1980213
references: Acta Crystallogr D Biol Crystallogr. 2004 Dec;60(Pt 12 Pt 1):2126-32
references: 15572765
references: Biochemistry. 1990 Dec 4;29(48):10745-57
references: 2125493
references: Nucleic Acids Res. 1998 Jul 15;26(14):3404-9
references: 9649626
references: Biochem J. 1976 Dec 1;159(3):689-95
references: 1008826
references: Biochemistry. 1969 Dec;8(12):5189-96
references: 5391873
references: Annu Rev Biophys Biomol Struct. 2001;30:191-209
references: 11340058