2.4.1.134 | malfunction |
loss of function of gene b3GalT6 causes a severe deficiency in glycosaminoglycan synthesis and results in the production of immature decorin, lacking its chondroitin sulfate/dermatan sulfate side chain, as well as reduced-to-absent heparan sulfate chains in dermal fibroblasts of affected individuals. Homozygosity mapping and candidate gene sequence analysis in three independent families identified biallelic gene B3GALT6 mutations, including homozygous missense, the families present a severe autosomal-recessive connective tissue disorder characterized by skin fragility, delayed wound healing, joint hyperlaxity and contractures, muscle hypotonia, intellectual disability, and a spondyloepimetaphyseal dysplasia with bone fragility and severe kyphoscoliosis. The phenotype overlaps with several recessive Ehlers-Danlos variants and spondyloepimetaphyseal dysplasia with joint hyperlaxity. Affected individuals' fibroblasts exhibit a large decrease in ability to prime glycosaminoglycan synthesis together with impaired glycanation of the small chondroitin/dermatan sulfate proteoglycan decorin, confirming b3GalT6 loss of function. Dermal electron microcopy discloses abnormalities in collagen fibril organization, in line with the important regulatory role of decorin in this process. A strong reduction in heparan sulfate level is also observed, indicating that enzyme b3GalT6 deficiency alters synthesis of both main types of glycosaminoglycans. In vitro wound healing assay reveals a significant delay in fibroblasts from two index individuals, pointing to a role for glycosaminoglycan defect in impaired wound repair in vivo. Genotype-Phenotype-analysis, overview |
735420 |