GBE1 – Glycogen Storage Disease Type IV

Glycogen branching enzyme 1 (GBE1) encodes the 1,4-α-glucan branching enzyme critical for normal glycogen architecture. Biallelic pathogenic variants in GBE1 cause glycogen storage disease type IV (GSD IV; MONDO:0009292), an autosomal recessive disorder characterized by storage of poorly branched polyglucosan in liver, muscle, heart, and other tissues. Clinical presentations range from the classic progressive hepatic cirrhosis form to perinatal/neonatal neuromuscular and adult polyglucosan body disease variants, reflecting allelic heterogeneity and residual enzyme activity.

1 Clinical Validity

The association between GBE1 and GSD IV is supported by multiple independent families with biallelic loss-of-function or hypomorphic variants and consistent autosomal recessive segregation ([PMID:8613547]). Functional studies across at least three unrelated presentations demonstrate concordant loss of GBE1 activity. Based on ClinGen criteria, the gene–disease association for GBE1 and GSD IV is Strong.

2 Genetic Evidence

GSD IV is inherited in an autosomal recessive pattern with compound heterozygous or homozygous variants. Over 40 distinct pathogenic variants spanning missense, nonsense, frameshift, and splice-site classes have been reported in affected individuals ([PMID:27107456]). One representative pathogenic variant is c.671T>C (p.Leu224Pro), which abolishes enzyme activity in transient expression assays. Segregation of biallelic variants in siblings has been documented (one additional affected relative in sibship) and variant spectrum reaches the genetic evidence cap under ClinGen guidelines.

3 Functional Evidence

Enzyme assays of patient-derived cells and transient expression in vitro confirm that classical mutations such as p.Leu224Pro and p.Tyr329Ser result in complete loss of branching activity, whereas alleles like p.Tyr329Ser retain ~50% residual activity correlating with milder nonprogressive forms ([PMID:8613547]). More recently, iPSC-based models harboring novel variants (e.g., p.Ile694Asn) recapitulate polyglucosan accumulation in differentiated hepatocytes and cardiomyocytes, confirming loss of function and utility of patient-specific cellular models ([PMID:38516405]).

4 Genotype–Phenotype Correlations

Null and severe missense variants (e.g., p.Arg515His, p.Leu490fs) underlie the fatal congenital neuromuscular form, whereas alleles with residual activity (e.g., p.Tyr329Ser, p.Ala214Thr) present as nonprogressive hepatic or adult polyglucosan body phenotypes. Compound heterozygosity for a null and a hypomorphic allele often results in intermediate severity, guiding prognosis and management.

5 Diagnostic & Therapeutic Implications

Early molecular diagnosis via targeted GBE1 sequencing or panel/exome testing allows prenatal and preimplantation diagnosis, informs carrier screening in at-risk families, and guides organ transplantation decisions. Emerging small-molecule chaperones and peptide rescue strategies targeting misfolded GBE1 variants hold promise for future therapies.

6 Key Take-Home

GBE1 variants cause a spectrum of autosomal recessive GSD IV phenotypes; comprehensive genetic testing combined with functional assays is essential for precise diagnosis, prognostic counseling, and emerging personalized interventions.

References

• The Journal of Clinical Investigation • 1996 • Hepatic and neuromuscular forms of glycogen storage disease type IV caused by mutations in the same glycogen-branching enzyme gene. PMID:8613547
• Human pathology • 2016 • A novel GBE1 gene variant in a child with glycogen storage disease type IV. PMID:27107456
• Molecular genetics and metabolism reports • 2024 • Induced pluripotent stem cell (iPSC) modeling validates reduced GBE1 enzyme activity due to a novel variant, p.Ile694Asn, found in a patient with suspected glycogen storage disease IV. PMID:38516405

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