AGL – Glycogen Storage Disease Type III

AGL encodes the amylo-1,6-glucosidase, 4-α-glucanotransferase (glycogen debranching enzyme) responsible for complete glycogenolysis in liver and muscle. Biallelic pathogenic variants in AGL cause glycogen storage disease type III (GSD III), an autosomal recessive disorder with hepatomegaly, fasting hypoglycemia, and progressive myopathy/cardiomyopathy (PMID:8990006).

Inherited in an autosomal recessive manner, GSD IIIa patients present with both liver and muscle enzyme deficiency, whereas GSD IIIb patients have liver-only involvement due to exon 3 mutations causing tissue-specific splicing (PMID:8755644). Over 175 unrelated probands from 147 families have been reported with diverse loss-of-function and missense variants in AGL, including frameshifts, nonsense, splice-site, and the first identified insertion 4529insA (c.4529dup (p.Tyr1510Ter)) associated with a severe phenotype (PMID:8990006; PMID:27106217).

Recurrent and founder variants such as c.3216_3217del (p.Glu1072AspfsTer36) in Tunisia and p.W1327X in Turkish patients demonstrate population-specific allele frequencies and shared haplotypes, aiding molecular diagnostics (PMID:22035446; PMID:23207808).

Functional studies reveal that missense variants impair transferase (e.g., p.Leu620Pro) or glucosidase (e.g., p.Arg1147Gly) activities, whereas mutations in the carbohydrate-binding domain lead to complete loss of enzyme function and increased ubiquitin-proteasome degradation (PMID:19299494; PMID:17908927). Splice-site and intronic mutations (e.g., c.2682-8A>G) produce aberrant transcripts and truncated proteins, confirmed by RT-PCR in patient cells (PMID:23649758).

Genotype-phenotype correlations support that truncated C-terminal variants (e.g., c.3965delT) correlate with early onset and more severe disease, whereas certain missense or splice-site alleles confer milder courses (PMID:11949933; PMID:10655153).

Molecular diagnosis via full AGL gene sequencing complemented by targeted founder mutation screens enables noninvasive confirmation of GSD III, guiding dietary management (frequent feeds, uncooked cornstarch) and surveillance for liver, cardiac, and muscle complications.

Key Take-home: AGL gene sequencing is clinically essential for definitive diagnosis of GSD III, informs prognosis based on variant class, and supports tailored management to prevent hypoglycemia and organ damage.

References

• Human mutation • 1997 • A nonsense mutation due to a single base insertion in the 3'-coding region of glycogen debranching enzyme gene associated with a severe phenotype in a patient with glycogen storage disease type IIIa. PMID:8990006
• The Journal of clinical investigation • 1996 • 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. PMID:8755644
• Journal of inherited metabolic disease • 2016 • Glycogen storage disease type III: diagnosis, genotype, management, clinical course and outcome. PMID:27106217
• Molecular biology reports • 2013 • Molecular and biochemical characterization of a novel intronic single point mutation in a Tunisian family with glycogen storage disease type III. PMID:23649758
• Human molecular genetics • 2009 • Distinct mutations in the glycogen debranching enzyme found in glycogen storage disease type III lead to impairment in diverse cellular functions. PMID:19299494
• Genes & development • 2007 • A role for AGL ubiquitination in the glycogen storage disorders of Lafora and Cori's disease. PMID:17908927

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