Mutations in B3GALT6, which Encodes a Glycosaminoglycan Linker Region Enzyme, Cause a Spectrum of Skeletal and Connective Tissue Disorders
Open accessAbstract
Proteoglycans (PGs) are a major component of the extracellular matrix in many tissues and function as structural and regulatory molecules. PGs are composed of core proteins and glycosaminoglycan (GAG) side chains. The biosynthesis of GAGs starts with the linker region that consists of four sugar residues and is followed by repeating disaccharide units. By exome sequencing, we found that B3GALT6 encoding an enzyme involved in the biosynthesis of the GAG linker region is responsible for a severe skeletal dysplasia, spondyloepimetaphyseal dysplasia with joint laxity type 1 (SEMD-JL1). B3GALT6 loss-of-function mutations were found in individuals with SEMD-JL1 from seven families. In a subsequent candidate gene study based on the phenotypic similarity, we found that B3GALT6 is also responsible for a connective tissue disease, Ehlers-Danlos syndrome (progeroid form). Recessive loss-of-function mutations in B3GALT6 result in a spectrum of disorders affecting a broad range of skeletal and connective tissues characterized by lax skin, muscle hypotonia, joint dislocation, and spinal deformity. The pleiotropic phenotypes of the disorders indicate that B3GALT6 plays a critical role in a wide range of biological processes in various tissues, including skin, bone, cartilage, tendon, and ligament.
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Also using recombinant proteins, they reported that both enzyme mutants (p.(Ser65Gly), p.(Pro67Leu)) were inactive, emphasizing the role of the conserved N-terminal end of the catalytic domain in the functional activity of the enzyme.
“Also using recombinant proteins, they reported that both enzyme mutants (p.(Ser65Gly), p.(Pro67Leu)) were inactive, emphasizing the role of the conserved N-terminal end of the catalytic domain in the functional activity of the enzyme.”
From The Ehlers–Danlos syndromes, rare types (2017) · cites this paper as Nakajima et al., 2013
Nakajima et al. [2013] identified B3GALT6 mutations in seven Japanese families with spondyloepimetaphyseal dysplasia with joint laxity type 1 (SEMD-JL1) by whole exome sequencing.
“Nakajima et al. [2013] identified B3GALT6 mutations in seven Japanese families with spondyloepimetaphyseal dysplasia with joint laxity type 1 (SEMD-JL1 or SEMD-JL Beighton type) by whole exome sequencing.”
From The Ehlers–Danlos syndromes, rare types (2017) · cites this paper as Nakajima et al., 2013
Nakajima et al. [2013] showed that a recombinant mutant lacking the initiation codon (p.Met1) produced a truncated protein that was mislocalized to the cytoplasm and nucleus, presumably inactive.
“Nakajima et al. [2013] showed that a recombinant mutant, lacking the initiation codon (p.Met1) produced a truncated protein that was mislocalized to the cytoplasm and nucleus, presumably inactive.”
From The Ehlers–Danlos syndromes, rare types (2017) · cites this paper as Nakajima et al., 2013
In three other families with a phenotype resembling β4GalT7-deficient EDS, targeted B3GALT6 sequencing subsequently identified causal mutations in all of them.
“In three other families with a phenotype resembling b4GalT7-deficient EDS, targeted B3GALT6 sequencing subsequently identified causal mutations in all of them.”
From The Ehlers–Danlos syndromes, rare types (2017) · cites this paper as Nakajima et al., 2013
Cites
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Loss-of-function mutations of CHST14 in a new type of Ehlers-Danlos syndrome
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The Ehlers–Danlos syndromes, rare types
Brady, A. F., Demirdas, S., Fournel‐Gigleux, S., Ghali, N., Giunta, C., Kapferer‐Seebacher, I., Kosho, T., Mendoza‐Londono, R., Pope, M. F., Rohrbach, M., et al. (2017) · American Journal of Medical Genetics Part C Seminars in Medical Genetics · doi:10.1002/ajmg.c.31550 · Cited by 249 · see citing works
Self-citationColombi, M., Dordoni, C., Chiarelli, N., & Ritelli, M. (2015) · American Journal of Medical Genetics Part C: Seminars in Medical Genetics · doi:10.1002/ajmg.c.31429 · Cited by 127 · see citing works
Ehlers–Danlos syndrome: A showcase of conditions that lead to understanding matrix biology
Byers, P. H., & Murray, M. L. (2014) · Matrix Biology · doi:10.1016/j.matbio.2013.07.005 · Cited by 68 · see citing works
Human genetic disorders and knockout mice deficient in glycosaminoglycan
Mizumoto, S., Yamada, S., & Sugahara, K. (2014) · BioMed Research International · doi:10.1155/2014/495764 · Cited by 54 · see citing works
Self-citationGenetics of the Ehlers–Danlos syndrome: More than collagen disorders
Van Damme, T., Syx, D., Coucke, P., Symoens, S., De Paepe, A., & Malfait, F. (2015) · Expert Opinion on Orphan Drugs · doi:10.1517/21678707.2015.1022528 · Cited by 4 · see citing works
- Authors
- Nakajima, M., Mizumoto, S., Miyake, N., Kogawa, R., Iida, A., Ito, H., Kitoh, H., Hirayama, A., Mitsubuchi, H., Miyazaki, O., Kosaki, R., Horikawa, R., Lai, A., Mendoza-Londono, R., Dupuis, L., Chitayat, D., Howard, A., Leal, G. F., Cavalcanti, D., Tsurusaki, Y., Saitsu, H., Watanabe, S., Lausch, E., Unger, S., Bonafé, L., Ohashi, H., Superti-Furga, A., Matsumoto, N., Sugahara, K., Nishimura, G., & Ikegawa, S.
- Affiliations
- RIKEN (JP)
- Hokkaido University (JP)
- Yokohama City University (JP)
- Aichi Developmental Disability Center (JP)
- Nagoya University (JP)
- Akita Prefectural Center on Development and Disability (JP)
- Kumamoto University Hospital (JP)
- National Center For Child Health and Development (JP)
- KK Women's and Children's Hospital (SG)
- University of Toronto (CA)
- Instituto de Medicina Integral Professor Fernando Figueira (BR)
- Universidade Estadual de Campinas (UNICAMP) (BR)
- Saitama Children's Medical Center (JP)
- University of Freiburg (DE)
- Centre Hospitalier Universitaire Vaudois (CH)
- Tokyo Metropolitan Children's Medical Center (JP)
- Corresponding author
- Ikegawa, Shiro
- ORCID
- Mizumoto, Shuji
- Miyake, Noriko
- Kogawa, Ryo
- Iida, Aritoshi
- Kitoh, Hiroshi
- Mitsubuchi, Hiroshi
- Miyazaki, Osamu
- Kosaki, Rika
- Horikawa, Reiko
- Lai, Angeline
- Dupuis, Lucie
- Chitayat, David
- Howard, Andrew
- Cavalcanti, Denise
- Tsurusaki, Yoshinori
- Saitsu, Hirotomo
- Unger, Sheila
- Ohashi, Hirofumi
- Matsumoto, Naomichi
- Sugahara, Kazuyuki
- Nishimura, Gen
- Ikegawa, Shiro
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2013-06
- Volume
- 92
- Issue
- 6
- Pages
- 927-934
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC3675233
- OpenAlex
- W1987054961
- Cited by
- 137
- References
- 3
- Citations by year
- 2026: 7 · 2025: 6 · 2024: 9 · 2023: 4 · 2022: 12 · 2021: 12 · 2020: 12 · 2019: 13 · 2018: 9 · 2017: 9 · 2016: 18 · 2015: 11 · 2014: 8 · 2013: 6
- FWCI
- 8.32
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- IRIS (submittedVersion)
- SERVAL (Université de Lausanne) (submittedVersion)
- Funders
- Ministry of Health, Labour and Welfare (23300101, 23300201, 23689052, 23790066)
- Fondation Leenaards (H23-Nanchi-Ippan-123)
- Akiyama Life Science Foundation
- Japan Society for the Promotion of Science
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (310030_132940, 31003A_141241)
- Ministry of Education, Culture, Sports, Science and Technology
- 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 › Rheumatology › Glycogen Storage Diseases and Myoclonus
- Keywords
- B3GALT6, glycosaminoglycan synthesis, skeletal dysplasia, connective tissue diseases, loss-of-function mutations, pleiotropy, skin laxity, joint dislocation, spinal deformity, exome sequencing, candidate gene association
- MeSH terms
- Abnormalities, Multiple, Adult, Child, Child, Preschool, Female, Galactosyltransferases, Glycosaminoglycans, Humans, Joint Instability, Male, Osteochondrodysplasias, Sequence Analysis, DNA, Mutation, Missense, Genetic Association Studies, High-Throughput Nucleotide Sequencing
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