GYG1 – Glycogen storage disease XV

Glycogen storage disease XV (GSD XV) is an autosomal recessive muscle glycogenosis caused by biallelic variants in GYG1. Affected individuals present with limb-girdle muscle weakness, early exertional myalgia, waddling gait, scapular winging, and polyglucosan inclusions on muscle biopsy. Serum creatine kinase is mildly elevated and muscle MRI shows selective fatty replacement of proximal and axial muscles. Electron microscopy confirms PAS-positive, α-amylase-resistant polyglucosan bodies, distinguishing GSD XV from dystrophic processes (PMID:32477874).

Biallelic GYG1 variants have been reported in three unrelated probands, including compound heterozygous missense and frameshift alleles and a splice-site mutation (PMID:32477874; PMID:31791869). Segregation of two heterozygous variants co-segregating with disease was observed in a family with two affected siblings (PMID:29143313). Recurrent variants include c.304G>C (p.Asp102His), which is associated with both myopathic and cardiomyopathic presentations.

The variant spectrum comprises at least three missense changes (p.Asp102His, p.His212Tyr, p.Gly135Arg), four loss-of-function alleles (p.Asp163ThrfsTer5, p.Val211CysfsTer30, c.144-2A>G, c.484delG), and a splice acceptor mutation. The recurrent p.Asp102His allele suggests a genotype–phenotype correlation influencing cardiomyopathy risk in homozygosity.

Functional analyses demonstrate absent or reduced non-functional glycogenin-1 protein in patient muscle, with PAS-positive polyglucosan aggregates resistant to α-amylase (PMID:31791869; PMID:26255073). In vitro autoglucosylation assays of recombinant mutants (His212Tyr, Gly135Arg) confirm loss of primer activity and support an inter-subunit glucosylation mechanism critical for normal glycogen initiation (PMID:10049511).

No conflicting evidence has been reported disputing the primary association between GYG1 loss-of-function and GSD XV. Experimental findings across histopathology, biochemical, and cellular assays are concordant with the human phenotype.

Key take-home: Biallelic GYG1 variants cause AR polyglucosan myopathy (GSD XV); inclusion of GYG1 in LGMD, distal myopathy, and metabolic myopathy gene panels enhances diagnostic yield and informs patient management.

References

• Molecular Genetics and Metabolism Reports • 2020 • Glycogenin-1 deficiency mimicking limb-girdle muscular dystrophy. PMID:32477874
• Neuromuscular Disorders • 2019 • Functional characterization of GYG1 variants in two patients with myopathy and glycogenin-1 deficiency. PMID:31791869
• Acta Neurologica Scandinavica • 2018 • Polyglucosan myopathy and functional characterization of a novel GYG1 mutation. PMID:29143313
• Neuromuscular Disorders • 2015 • Muscle pathology and whole-body MRI in a polyglucosan myopathy associated with a novel glycogenin-1 mutation. PMID:26255073
• Archives of Biochemistry and Biophysics • 1999 • Self-glucosylation of glycogenin, the initiator of glycogen biosynthesis, involves an inter-subunit reaction. PMID:10049511

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