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Defective initiation of glycosaminoglycan synthesis due to B3GALT6 mutations causes a pleiotropic Ehlers-Danlos-syndrome-like connective tissue disorder

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Abstract
Proteoglycans are important components of cell plasma membranes and extracellular matrices of connective tissues. They consist of glycosaminoglycan chains attached to a core protein via a tetrasaccharide linkage, whereby the addition of the third residue is catalyzed by galactosyltransferase II (beta 3GalT6), encoded by B3GALT6. Homozygosity mapping and candidate gene sequence analysis in three independent families, presenting 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, identified biallelic B3GALT6 mutation's, including homozygous missense mutations in family 1 (c.619G>C [p.Asp207His]) and family 3 (c.649G>A [p.Gly217Ser]) and compound heterozygous mutations in family 2 (c.323_344del [p.Ala108Glyfs*163], c.619G>C [p.Asp207His]). The phenotype overlaps with several recessive Ehlers-Danlos variants and spondyloepimetaphyseal dysplasia with joint hyperlaxity. Affected individuals' fibroblasts exhibited a large decrease in ability to prime glycosaminoglycan synthesis together with impaired glycanation of the small chondroitin/dermatan sulfate proteoglycan decorin, confirming beta 3GalT6 loss of function. Dermal electron microcopy disclosed abnormalities in collagen fibril organization, in line with the important regulatory role of decorin in this process. A strong reduction in heparan sulfate level was also observed, indicating that beta 3GalT6 deficiency alters synthesis of both main types of glycosaminoglycans. In vitro wound healing assay revealed a significant delay in fibroblasts from two index individuals, pointing to a role for glycosaminoglycan defect in impaired wound repair in vivo. Our study emphasizes a crucial role for beta 3GalT6 in multiple major developmental and pathophysiological processes.
Keywords
PROTEIN LINKAGE REGION, THUMB-CLUBFOOT SYNDROME, TENASCIN-X DEFICIENCY, OF-FUNCTION MUTATIONS, COLLAGEN TYPE-VI, HEPARAN-SULFATE, GALACTOSYLTRANSFERASE-II, PROGRESSIVE KYPHOSCOLIOSIS, MOLECULAR-CLONING, JOINT LAXITY

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Chicago
Malfait, Fransiska, Ariana Kariminejad, Tim Van Damme, Caroline Gauche, Delfien Syx, Faten Merhi-Soussi, Sandrine Gulberti, et al. 2013. “Defective Initiation of Glycosaminoglycan Synthesis Due to B3GALT6 Mutations Causes a Pleiotropic Ehlers-Danlos-syndrome-like Connective Tissue Disorder.” American Journal of Human Genetics 92 (6): 935–945.
APA
Malfait, Fransiska, Kariminejad, A., Van Damme, T., Gauche, C., Syx, D., Merhi-Soussi, F., Gulberti, S., et al. (2013). Defective initiation of glycosaminoglycan synthesis due to B3GALT6 mutations causes a pleiotropic Ehlers-Danlos-syndrome-like connective tissue disorder. AMERICAN JOURNAL OF HUMAN GENETICS, 92(6), 935–945.
Vancouver
1.
Malfait F, Kariminejad A, Van Damme T, Gauche C, Syx D, Merhi-Soussi F, et al. Defective initiation of glycosaminoglycan synthesis due to B3GALT6 mutations causes a pleiotropic Ehlers-Danlos-syndrome-like connective tissue disorder. AMERICAN JOURNAL OF HUMAN GENETICS. 2013;92(6):935–45.
MLA
Malfait, Fransiska, Ariana Kariminejad, Tim Van Damme, et al. “Defective Initiation of Glycosaminoglycan Synthesis Due to B3GALT6 Mutations Causes a Pleiotropic Ehlers-Danlos-syndrome-like Connective Tissue Disorder.” AMERICAN JOURNAL OF HUMAN GENETICS 92.6 (2013): 935–945. Print.
@article{4106905,
  abstract     = {Proteoglycans are important components of cell plasma membranes and extracellular matrices of connective tissues. They consist of glycosaminoglycan chains attached to a core protein via a tetrasaccharide linkage, whereby the addition of the third residue is catalyzed by galactosyltransferase II (beta 3GalT6), encoded by B3GALT6. Homozygosity mapping and candidate gene sequence analysis in three independent families, presenting 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, identified biallelic B3GALT6 mutation's, including homozygous missense mutations in family 1 (c.619G>C [p.Asp207His]) and family 3 (c.649G>A [p.Gly217Ser]) and compound heterozygous mutations in family 2 (c.323_344del [p.Ala108Glyfs*163], c.619G>C [p.Asp207His]). The phenotype overlaps with several recessive Ehlers-Danlos variants and spondyloepimetaphyseal dysplasia with joint hyperlaxity. Affected individuals' fibroblasts exhibited a large decrease in ability to prime glycosaminoglycan synthesis together with impaired glycanation of the small chondroitin/dermatan sulfate proteoglycan decorin, confirming beta 3GalT6 loss of function. Dermal electron microcopy disclosed abnormalities in collagen fibril organization, in line with the important regulatory role of decorin in this process. A strong reduction in heparan sulfate level was also observed, indicating that beta 3GalT6 deficiency alters synthesis of both main types of glycosaminoglycans. In vitro wound healing assay revealed a significant delay in fibroblasts from two index individuals, pointing to a role for glycosaminoglycan defect in impaired wound repair in vivo. Our study emphasizes a crucial role for beta 3GalT6 in multiple major developmental and pathophysiological processes.},
  author       = {Malfait, Fransiska and Kariminejad, Ariana and Van Damme, Tim and Gauche, Caroline and Syx, Delfien and Merhi-Soussi, Faten and Gulberti, Sandrine and Symoens, Sofie and Vanhauwaert, Suzanne and Willaert, Andy and Bozorgmehr, Bita and Kariminejad, Mohamad Hasan and Ebrahimiadib, Nazanin and Hausser, Ingrid and Huysseune, Ann and Fournel-Gigleux, Sylvie and De Paepe, Anne},
  issn         = {0002-9297},
  journal      = {AMERICAN JOURNAL OF HUMAN GENETICS},
  keywords     = {PROTEIN LINKAGE REGION,THUMB-CLUBFOOT SYNDROME,TENASCIN-X DEFICIENCY,OF-FUNCTION MUTATIONS,COLLAGEN TYPE-VI,HEPARAN-SULFATE,GALACTOSYLTRANSFERASE-II,PROGRESSIVE KYPHOSCOLIOSIS,MOLECULAR-CLONING,JOINT LAXITY},
  language     = {eng},
  number       = {6},
  pages        = {935--945},
  title        = {Defective initiation of glycosaminoglycan synthesis due to B3GALT6 mutations causes a pleiotropic Ehlers-Danlos-syndrome-like connective tissue disorder},
  url          = {http://dx.doi.org/10.1016/j.ajhg.2013.04.016},
  volume       = {92},
  year         = {2013},
}

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