B3GALNT2 – muscular dystrophy-dystroglycanopathy, type A

B3GALNT2 encodes the β-1,3-N-acetylgalactosaminyltransferase 2 enzyme required for glycosylation of α-dystroglycan. Aberrant glycosylation of α-dystroglycan underlies a spectrum of congenital muscular dystrophy-dystroglycanopathies, including muscle-eye-brain disease and Walker–Warburg syndrome. Muscular dystrophy-dystroglycanopathy, type A, is characterized by early hypotonia, progressive muscle weakness, brain malformations, and sometimes ocular involvement.[PMID:24084573]

Autosomal recessive B3GALNT2 variants have been reported in 8 unrelated probands across 5 studies, including compound heterozygous and homozygous configurations.[PMID:23453667];[PMID:24084573];[PMID:29791932];[PMID:35456500];[PMID:35338537] The index case was a 5-year-old girl with psychomotor retardation, ataxia, spasticity, muscle weakness, and hypoglycosylation of α-dystroglycan on muscle histochemistry.[PMID:24084573] A second child presented with severe muscle-eye-brain disease featuring microphthalmia, blindness, hypotonia, and refractory epilepsy carrying a homozygous nonsense variant.[PMID:29791932]

Segregation analysis in consanguineous and non-consanguineous families identified 7 additional affected relatives with co-segregating B3GALNT2 alleles, supporting autosomal recessive inheritance. Variant spectrum includes loss-of-function alleles (nonsense, frameshift, splice) and missense changes in catalytic domains. One recurrent stop codon, c.448C>T (p.Arg150Ter), has been observed in multiple pedigrees, suggesting possible founder effects in certain populations.

Functional studies demonstrate that patient fibroblasts and muscle exhibit severely reduced α-dystroglycan glycosylation and laminin binding. B3GALNT2 knockdown in zebrafish recapitulates the human muscular dystrophy phenotype with disordered muscle fibers, brain abnormalities, and reduced motility.[PMID:23453667] Missense mutations perturb enzyme localization to the endoplasmic reticulum and reduce catalytic activity, consistent with a haploinsufficiency mechanism.

Overall, the clinical validity of the B3GALNT2–muscular dystrophy-dystroglycanopathy, type A association is Strong by ClinGen criteria, supported by >8 probands in multiple families, segregation, and concordant functional data. Genetic evidence meets a Strong tier, and experimental assays confer Moderate functional support. B3GALNT2 testing is clinically useful for diagnosis, genetic counseling, and prenatal assessment in dystroglycanopathies.

Key Take-home: B3GALNT2 pathogenic variants cause autosomal recessive muscular dystrophy-dystroglycanopathy, type A, reliably diagnosed by sequencing and confirmed by glycosylation assays.

References

• European journal of human genetics • 2014 • B3GALNT2 is a gene associated with congenital muscular dystrophy with brain malformations. PMID:24084573
• American journal of human genetics • 2013 • Mutations in B3GALNT2 cause congenital muscular dystrophy and hypoglycosylation of α-dystroglycan PMID:23453667
• Neuropediatrics • 2018 • B3GALNT2-Related Dystroglycanopathy: Expansion of the Phenotype with Novel Mutation Associated with Muscle-Eye-Brain Disease, Walker-Warburg Syndrome, Epileptic Encephalopathy-West Syndrome, and Sensorineural Hearing Loss. PMID:29791932
• Journal of neuromuscular diseases • 2025 • Pathogenic mechanisms and clinical insights into B3GALNT2-related alpha-dystroglycanopathies. PMID:40665687

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