B3GALT6 – Spondyloepimetaphyseal Dysplasia with Joint Laxity

B3GALT6 encodes β3GalT6, a galactosyltransferase critical for initiating glycosaminoglycan (GAG) chain synthesis on proteoglycans. Pathogenic biallelic variants in B3GALT6 cause spondyloepimetaphyseal dysplasia with joint laxity (SEMD-JL1), a rare autosomal recessive skeletal dysplasia with connective tissue involvement. Patients present with severe joint hypermobility, skeletal dysplasia, bone fragility, and variable extra-skeletal features including skin fragility and cardiovascular complications.

Genetic evidence includes 3 unrelated probands with homozygous missense and frameshift variants (e.g., c.619G>C (p.Asp207His)) demonstrating autosomal recessive segregation (3 probands [PMID:23664118]), 12 additional patients in multi-center cohorts (12 probands [PMID:29931299]), and 3 illustrative cases spanning the SEMD-JL1 to EDS spectrum (3 probands [PMID:37657630]). The variant spectrum comprises missense (e.g., c.619G>C (p.Asp207His), c.649G>A (p.Gly217Ser)) and frameshift alleles (e.g., c.323_344del (p.Ala108GlyfsTer163)), with both private and recurrent mutations.

Functional studies show that β3GalT6 deficiency leads to a profound reduction in GAG linkage region formation, impaired chondroitin/dermatan sulfate proteoglycan glycanation, and decreased heparan sulfate levels ([PMID:23664118]). Dermal fibroblasts exhibit collagen fibril disorganization on electron microscopy, mirroring the connective tissue phenotype. In vitro wound healing assays demonstrate delayed fibroblast migration, linking the biochemical defect to clinical skin and joint laxity.

Multi-patient and expression profiling studies reveal downstream perturbation of extracellular matrix genes (COMP, SPP1, COL5A1) and signaling pathways (GDF6, GDF15, BMPER) consistent with skeletal and connective tissue involvement ([PMID:28649518]). Recent cohort analyses underscore overlapping SEMD-JL1 and spondylodysplastic EDS features, including aortic dilation and cervical spine instability, broadening the phenotype.

Integration of genetic and experimental data confirms loss-of-function as the pathogenic mechanism. The consistency of autosomal recessive segregation, variant spectrum, and functional concordance supports a definitive gene–disease relationship. B3GALT6 testing should be included in diagnostic panels for skeletal dysplasia and connective tissue disorders.

Key Take-home: B3GALT6 biallelic loss-of-function variants cause definitive autosomal recessive SEMD-JL1 with characteristic skeletal and connective tissue manifestations, enabling targeted genetic diagnosis.

References

• American Journal of Human Genetics • 2013 • Defective initiation of glycosaminoglycan synthesis due to B3GALT6 mutations causes a pleiotropic Ehlers-Danlos-syndrome-like connective tissue disorder. PMID:23664118
• Human Molecular Genetics • 2018 • Biallelic B3GALT6 mutations cause spondylodysplastic Ehlers-Danlos syndrome. PMID:29931299
• European Journal of Medical Genetics • 2023 • B3GALT6-linkeropathy: Three illustrative patients spanning the disease spectrum. PMID:37657630

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