B3GALNT2 – Muscle-eye-brain Disease

B3GALNT2 encodes β-1,3-N-acetylgalactosaminyltransferase 2, an enzyme required for glycosylation of α-dystroglycan. Autosomal recessive muscle-eye-brain (MEB) disease (MONDO:0018939) is characterized by congenital muscular dystrophy, brain malformations, and variable ocular involvement, mapping to biallelic B3GALNT2 mutations.

Genetic evidence supports a strong gene–disease association. In total, eight unrelated probands have been reported: two singleton case reports (compound heterozygous and homozygous) (PMID:24084573), and six individuals from a multi-patient dystroglycanopathy cohort (PMID:23453667). Segregation analysis in two multiplex families demonstrated seven additional affected relatives (PMID:29273094). A recurrent missense variant, c.979G>A (p.Asp327Asn), and multiple loss-of-function alleles have been described across studies.

The clinical spectrum of B3GALNT2-related MEB includes early onset hypotonia, spasticity, ataxia, and muscle weakness, often accompanied by eye anomalies (microphthalmia, blindness) and sensorineural hearing impairment. Brain MRI typically reveals white matter signal changes, pontocerebellar hypoplasia, and cerebellar cysts.

Functional assays demonstrate hypoglycosylation of α-dystroglycan in patient fibroblasts and muscle by immunohistochemistry, immunoblotting, and laminin overlay (PMID:23453667). B3GALNT2 localizes to the endoplasmic reticulum, and missense mutations perturb this localization. Knockdown of b3galnt2 in zebrafish recapitulates muscular dystrophy, brain malformations, and reduced motility, confirming pathogenicity.

The pathogenic mechanism is loss of glycosyltransferase activity leading to deficient α-dystroglycan laminin binding. Both truncating and deleterious missense variants result in haploinsufficiency below a functional threshold, consistent with an autosomal recessive model.

Overall, the cumulative genetic and experimental evidence assigns a strong level of clinical validity to B3GALNT2 in autosomal recessive MEB disease. B3GALNT2 sequencing and variant interpretation are recommended in patients presenting with congenital muscular dystrophy and brain malformations.

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
• Genome Medicine • 2017 • B3GALNT2 mutations associated with non-syndromic autosomal recessive intellectual disability reveal a lack of genotype-phenotype associations in the muscular dystrophy-dystroglycanopathies PMID:29273094

Evidence Based Scoring (AI generated)