Molecular Cloning, Sequencing, and Analysis of the cDNA for Rabbit Muscle Glycogen Debranching Enzyme

Liu, W.; Decastro, M.L.; Takrama, Jemmy; Bilous, P T; Vinayagamoorthy, T.; Madsen, Neil B.; Bleackley, R. Chris

doi:10.1006/abbi.1993.1505

Cited by 36 publications

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“…Glycogenosis type III (GSD III or Cori disease; MIM# 232400) is an autosomal recessive disorder of carbohydrate metabolism, altered in the last step of glycogen degradation, the essential deficiency regarding the glycogen debranching enzyme (AGL) Liu et al, 1993). This protein of approximately 160 kDa provides two different and separate catalytic activities: amylo-1,6-glucosidase (EC 3.2.1.33) in the C-terminal half, including the glycogen binding site, and 4-α-glucanotransferase (EC 2.4.1.25) in the N-terminal half (White et al, 1974;Bates et al, 1975;Bao et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

Hepatic and neuromuscular forms of glycogenosis type III: nine mutations inAGL

et al. 2006

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Glycogenosis type III (Cori disease) is an autosomal recessive disorder caused by the deficiency of the glycogen debranching enzyme, encoded by the AGL gene, and existing in six isoforms alternately spliced in a tissue-specific way. Generally, disease onset occurs early on starting from the first year of life, with hepatomegaly, hypoglycemia, hyperlipidemia, increased CK levels, and, in some cases, short stature and slight mental retardation. Frequently, hepatomegaly tends to resolve spontaneously and inexplicably during childhood, when myopathy, often associated with cardiomyopathy, arises. This disease is known to lack almost invariably clear links between the genotype and clinical phenotype. We describe nine new mutations in Italian patients: four nonsense (p.Arg285X, p.Lys422X, p.Arg910X, p.Arg977X), three frameshift (c.442delA, c.753_756delGACA, c.3963delG), and two missense (p.Ala1120Pro, p.Arg524His). Particularly, the nonsense p.Arg285X is linked to an exonic splicing enhancer and it was found to produce two species of transcripts at the same time. Moreover, we discuss a subgroup of subjects carrying c.2681+1G>A, which has proven to be the most frequent mutation among our patients. The previously described c.664+3A>G was also detected in two patients, both homozygous. The present work is yet another confirmation that the individual genetic background plays a pivotal role in influencing the phenotypes, as occurs in other metabolic diseases.

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Section: Introductionmentioning

confidence: 99%

Hepatic and neuromuscular forms of glycogenosis type III: nine mutations inAGL

et al. 2006

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“…We and others have isolated the GDE gene and determined its cDNA sequences (6,7). The GDE gene mRNA consists of a 4596-bp coding region and a 2371-bp 3 Ј -nontranslated region.…”

Section: Introductionmentioning

confidence: 99%

Mutations in exon 3 of the glycogen debranching enzyme gene are associated with glycogen storage disease type III that is differentially expressed in liver and muscle.

Shen¹,

Bao²,

Liu³

et al. 1996

J. Clin. Invest.

127

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Glycogen storage disease type III (GSD-III), an autosomal recessive disease, is caused by deficient glycogen debranching enzyme (GDE) activity. Most GSD-III patients are GDE deficient in both liver and muscle (type IIIa), and some GSD-III patients have GDE absent in liver but retained in muscle (type IIIb). The molecular basis for this enzymatic variability is largely unknown. In the present study, the analysis of the GDE gene in three GSD-IIIb patients by single-strand conformation polymorphism (SSCP), DNA sequencing, restriction analysis, and family studies, revealed each of them as being a compound heterozygote for two different mutations. The first mutant alleles in all three patients involved mutations in exon 3 at amino acid codon 6 of the GDE protein. Two had an AG deletion at nucleotides 17 and 18 of the GDE cDNA (17delAG) which resulted in change of subsequent amino acid sequence and a truncated protein (25X); the other had a C to T transition at nucleotide 16 of the cDNA which changed a Glutamine codon to a stop codon (Q6X). The 17delAG mutation was also found in 8 of the 10 additional GSD-IIIb patients. The Q6X mutation was found in one of the remaining two GSD-IIIb patients. These two mutations were not found in any of the 31 GSD-IIIa patients, 2 GSD-IIId patients, nor 28 unrelated normal controls. The second mutant alleles in each of the three GSD-IIIb patients were R864X, R1228X, and W680X. The R864X and R1228X were not unique for GSD-IIIb as they were also found in GSD-IIIa patients (frequency of 10.3% and 5.2% in Caucasian patients, respectively). Our data demonstrated that both IIIa and IIIb had mutations in the same GDE gene and established for the first time the molecular basis of GSD-III that differentially expressed in liver and muscle. The striking and specific association of exon 3 mutations with GSD-IIIb may provide insight into mechanisms controlling tissue-specific expression of the GDE gene. The identification of exon 3 mutations has clinical significance as well because it distinguished GSD-IIIb from IIIa hence permitting diagnosis from a blood sample rather than a more invasive muscle biopsy.

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“…However, the amino acid sequence of yeast GDE (11) showed that its C-terminal half had no significant homology with other amylolytic enzymes except for the mammalian GDEs (10,12). Likewise, the amino acid sequence on the C-terminal half of GDE and ␣-1,6-glucosidase (isomaltase) from the same origin Saccharomyces cerevisiae D-346 showed no significant homology.…”

Section: Analysis Of the Amino Acid Sequences For The Prediction Of Amentioning

confidence: 99%

“…Liu et al (10) suggested that the C-terminal half might encompass the glucosidase activity. However, the amino acid sequence of yeast GDE (11) showed that its C-terminal half had no significant homology with other amylolytic enzymes except for the mammalian GDEs (10,12).…”

Section: Analysis Of the Amino Acid Sequences For The Prediction Of Amentioning

confidence: 99%

“…Liu et al (9) showed that the transferase activity was irreversibly inactivated by carbodiimide in the presence of amines without affecting the glucosidase activity and concluded the existence of two distinct active sites, although the locations were not defined. The amino acid sequence analysis of rabbit GDE indicated that the N-terminal half may encompass the transferase activity, leaving the glucosidase activity at the C-terminal half (10).…”

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Identification of the Catalytic Residues of Bifunctional Glycogen Debranching Enzyme

Nakayama

Yamamoto

Tabata

2001

Journal of Biological Chemistry

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Eukaryotic glycogen debranching enzyme (GDE) possesses two different catalytic activities (oligo-1,431,4-glucantransferase/amylo-1,6-glucosidase) on a single polypeptide chain. To elucidate the structure-function relationship of GDE, the catalytic residues of yeast GDE were determined by site-directed mutagenesis. Asp-535, Glu-564, and Asp-670 on the N-terminal half and Asp-1086 and Asp-1147 on the C-terminal half were chosen by the multiple sequence alignment or the comparison of hydrophobic cluster architectures among related enzymes. The five mutant enzymes, D535N, E564Q, D670N, D1086N, and D1147N were constructed. The mutant enzymes showed the same purification profiles as that of wild-type enzyme on ␤-CD-Sepharose-6B affinity chromatography. All the mutant enzymes possessed either transferase activity or glucosidase activity. Three mutants, D535N, E564Q, and D670N, lost transferase activity but retained glucosidase activity. In contrast, D1086N and D1147N lost glucosidase activity but retained transferase activity. Furthermore, the kinetic parameters of each mutant enzyme exhibiting either the glucosidase activity or transferase activity did not vary markedly from the activities exhibited by the wild-type enzyme. These results strongly indicate that the two activities of GDE, transferase and glucosidase, are independent and located at different sites on the polypeptide chain.

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Molecular Cloning, Sequencing, and Analysis of the cDNA for Rabbit Muscle Glycogen Debranching Enzyme

Cited by 36 publications

References 0 publications

Hepatic and neuromuscular forms of glycogenosis type III: nine mutations inAGL

Hepatic and neuromuscular forms of glycogenosis type III: nine mutations inAGL

Mutations in exon 3 of the glycogen debranching enzyme gene are associated with glycogen storage disease type III that is differentially expressed in liver and muscle.

Identification of the Catalytic Residues of Bifunctional Glycogen Debranching Enzyme

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