CoChat
Sign Up
Cited by 142Proteoglycans and glycosaminoglycans researchConnective tissue disorders researchLysosomal Storage Disorders Research

Defective Initiation of Glycosaminoglycan Synthesis due to B3GALT6 Mutations Causes a Pleiotropic Ehlers-Danlos-Syndrome-like Connective Tissue Disorder

Open access
Malfait, Fransiska, Kariminejad, Ariana, Van Damme, Tim, Gauche, Caroline, Syx, Delfien, Merhi-Soussi, Faten, Gulberti, Sandrine, Symoens, Sofie +9 more·2013·The American Journal of Human Genetics
DOI 10.1016/j.ajhg.2013.04.016PMC PMC3675258
Open this paper in CoChat — free accountOpen PDF

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 (β3GalT6), 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 mutations, 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 β3GalT6 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 β3GalT6 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 β3GalT6 in multiple major developmental and pathophysiological processes.

Integrity signals

Registry

Crossref · 10.1016/j.ajhg.2013.04.016

Cites

44 of 44 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

We couldn’t retrieve this paper’s full text, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Malfait et al. [2013] identified B3GALT6 mutations in three unrelated families with a pleiotropic EDS-like connective tissue disorder, characterized by severe kyphoscoliosis, joint hypermobility and contractures, multiple early-onset fractures, SEMD, skin fragility, and intellectual disability.

    “Coincidently, Malfait et al. [2013] identified B3GALT6 mutations in three unrelated families with a pleiotropic EDS-like connective tissue disorder, characterized by severe kyphoscoliosis, joint hypermobility and contractures, multiple early-onset fractures, SEMD, skin fragility, and intellectual disability.”

    From The Ehlers–Danlos syndromes, rare types (2017) · cites this paper as Malfait et al., 2013

  • This study also showed that the GAG defects were associated with abnormal collagen structure and delayed migration in a wound healing assay, emphasizing the role of GAG in collagen fibril formation, as well as in various physiological functions of connective tissue, such as cicatrisation.

    “This study also showed that the GAG defects were associated with abnormal collagen structure and delayed migration in a wound healing assay, emphasizing the role of GAG in collagen fibril formation, as well as in various physiological functions of connective tissue, such as cicatrisation.”

    From The Ehlers–Danlos syndromes, rare types (2017) · cites this paper as Malfait et al., 2013

  • Expression of both HS and CS GAG chains was affected in these patients.

    “Expression of both HS and CS GAG chains was affected in these patients.”

    From The Ehlers–Danlos syndromes, rare types (2017) · cites this paper as Malfait et al., 2013

  • Malfait et al. [2013] showed, using cultured dermal fibroblasts, that GAG synthesis and activity was strongly reduced by the homozygous or compound p.(Asp207His) mutation found in two patients, as well as by the homozygous p.(Gly217Ser) mutation present in one of the patients.

    “Malfait et al. [2013] showed, using cultured dermal fibroblasts, that GAG synthesis and activity was strongly reduced by the homozygous or compound p.(Asp207His) mutation found in two patients, as well as by the homozygous p.(Gly217Ser) mutation present in one of the patients.”

    From The Ehlers–Danlos syndromes, rare types (2017) · cites this paper as Malfait et al., 2013

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Related

Authors
Malfait, F., Kariminejad, A., Van Damme, T., Gauche, C., Syx, D., Merhi-Soussi, F., Gulberti, S., Symoens, S., Vanhauwaert, S., Willaert, A., Bozorgmehr, B., Kariminejad, M. H., Ebrahimiadib, N., Hausser, I., Huysseune, A., Fournel-Gigleux, S., & De Paepe, A.
Affiliations
  • Ghent University Hospital (BE)
  • Centre National de la Recherche Scientifique (FR)
  • Farabi Hospital (IR)
  • Heidelberg University (DE)
  • Ghent University (BE)
Corresponding author
Malfait, Fransiska
ORCID
Venue
The American Journal of Human Genetics
Publisher
Elsevier BV
Published
2013-06
Volume
92
Issue
6
Pages
935-945
ISSN
0002-9297 (ISSN-L)
DOI
10.1016/j.ajhg.2013.04.016
PMC
PMC3675258
OpenAlex
W1988255044
Cited by
142
References
44
Citations by year
2026: 4 · 2025: 4 · 2024: 11 · 2023: 10 · 2022: 12 · 2021: 18 · 2020: 11 · 2019: 14 · 2018: 12 · 2017: 7 · 2016: 12 · 2015: 17 · 2014: 7 · 2013: 3
FWCI
7.54
Type
journal article
Language
en
Open access
Licence
Locations
  • The American Journal of Human Genetics (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • HAL (submittedVersion)
  • Ghent University Academic Bibliography (Ghent University) (submittedVersion)
Funders
Agence Nationale de la Recherche (ANR-08-PCVI-0023)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Proteoglycans and glycosaminoglycans research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Connective tissue disorders research
  • Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
Keywords
B3GALT6, Ehlers-Danlos syndrome, connective tissue diseases, spondyloepimetaphyseal dysplasia, decorin, chondroitin sulfate, dermatan sulfate, heparan sulfate, glycosaminoglycan synthesis, collagen fibril organization, wound healing, intellectual disability, compound heterozygosity, missense mutations, loss of function
MeSH terms
Abnormalities, Multiple, Adult, Amino Acid Sequence, Base Sequence, Child, Consanguinity, Ehlers-Danlos Syndrome, Female, Galactosyltransferases, Glycosaminoglycans, Humans, Infant, Male, Molecular Sequence Data, Pedigree, Radiography, Wound Healing, Sequence Analysis, DNA, Mutation, Missense, Genetic Association Studies, Genetic Pleiotropy

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review