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Cited by 287Trace Elements in HealthConnective tissue disorders researchIron Metabolism and Disorders

The Zinc Transporter SLC39A13/ZIP13 Is Required for Connective Tissue Development; Its Involvement in BMP/TGF-β Signaling Pathways

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Fukada, Toshiyuki, Civic, Natacha, Furuichi, Tatsuya, Shimoda, Shinji, Mishima, Kenji, Higashiyama, Hiroyuki, Idaira, Yayoi, Asada, Yoshinobu +18 more·2008·PLoS ONE
DOI 10.1371/journal.pone.0003642PMC PMC2575416
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Abstract

BACKGROUND: Zinc (Zn) is an essential trace element and it is abundant in connective tissues, however biological roles of Zn and its transporters in those tissues and cells remain unknown. METHODOLOGY/PRINCIPAL FINDINGS: Here we report that mice deficient in Zn transporter Slc39a13/Zip13 show changes in bone, teeth and connective tissue reminiscent of the clinical spectrum of human Ehlers-Danlos syndrome (EDS). The Slc39a13 knockout (Slc39a13-KO) mice show defects in the maturation of osteoblasts, chondrocytes, odontoblasts, and fibroblasts. In the corresponding tissues and cells, impairment in bone morphogenic protein (BMP) and TGF-beta signaling were observed. Homozygosity for a SLC39A13 loss of function mutation was detected in sibs affected by a unique variant of EDS that recapitulates the phenotype observed in Slc39a13-KO mice. CONCLUSIONS/SIGNIFICANCE: Hence, our results reveal a crucial role of SLC39A13/ZIP13 in connective tissue development at least in part due to its involvement in the BMP/TGF-beta signaling pathways. The Slc39a13-KO mouse represents a novel animal model linking zinc metabolism, BMP/TGF-beta signaling and connective tissue dysfunction.

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  • The second SLC39A13 mutation, homozygous missense c.221G>A, p.(Gly64Asp), has been identified in two siblings from Portugal.

    “The second mutation, a homozygous missense variant c.221G>A, p.(Gly64Asp) [Bin et al., 2011] has been identified in two siblings from Portugal”

    From The Ehlers–Danlos syndromes, rare types (2017) · cites this paper as Fukada et al., 2008

    The Results report that both affected siblings were homozygous for SLC39A13 c.221G>A, and the Case reports say their parents came from Portugal. However, the Results identify the predicted substitution as Gly74Asp (G74D), not Gly64Asp. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • To date, eight patients with spEDS-SLC39A13 from three independent families have been described: three pediatric, two adolescents, and three adults.

    “To date, eight patients with spEDS-SLC39A13 from three independent families have been described: Three pediatric (<12 years), two adolescents (12.5 and 14.5 years), and three adults (>20 years)”

    From The Ehlers–Danlos syndromes, rare types (2017) · cites this paper as Fukada et al., 2008

    The Case reports section (page unavailable) describes two affected adult siblings in one family, and the Discussion (page unavailable) reports two additional families described by Giunta et al. Our copy does not give a total of eight patients or the claimed breakdown of three pediatric patients, two adolescents, and three adults. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • A Slc39a13-/- knockout mouse recapitulated defects observed in patients, demonstrating that mutations in SLC39A13 cause Spondylocheirodysplastic EDS.

    “The authors furthermore generated a Slc39a13À/À knockout mouse that recapitulated defects observed in the patients, thereby demonstrating that mutations in SLC39A13 cause Spondylocheiro-dysplastic EDS”

    From The Ehlers–Danlos syndromes, rare types (2017) · cites this paper as Fukada et al., 2008

  • Fukada et al. [2008] reported a third family with two affected siblings with similar clinical findings who were homozygous for a missense mutation in SCL39A13.

    “Subsequently, Fukada et al. [2008] reported a third family with two affected siblings presenting with similar clinical findings who were homozygous for a missense mutation in SCL39A13”

    From The Ehlers–Danlos syndromes, rare types (2017) · cites this paper as Fukada et al., 2008

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References 85 · Cited by 287

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Authors
Fukada, T., Civic, N., Furuichi, T., Shimoda, S., Mishima, K., Higashiyama, H., Idaira, Y., Asada, Y., Kitamura, H., Yamasaki, S., Hojyo, S., Nakayama, M., Ohara, O., Koseki, H., dos Santos, H. G., Bonafe, L., Ha-Vinh, R., Zankl, A., Unger, S., Kraenzlin, M. E., Beckmann, J. S., Saito, I., Rivolta, C., Ikegawa, S., Superti-Furga, A., & Hirano, T.
Affiliations
  • RIKEN (JP)
  • University of Lausanne (CH)
  • Tsurumi University (JP)
  • Kazusa DNA Research Institute (JP)
  • University Hospital of Basel (CH)
  • Centre Hospitalier Universitaire Vaudois (CH)
  • Japan Science and Technology Agency (JP)
Corresponding author
Hirano, Toshio
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2008-11-05
Volume
3
Issue
11
Pages
e3642
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0003642
PMC
PMC2575416
OpenAlex
W2029900752
Cited by
287
References
85
Citations by year
2026: 8 · 2025: 16 · 2024: 14 · 2023: 11 · 2022: 12 · 2021: 9 · 2020: 19 · 2019: 20 · 2018: 18 · 2017: 24 · 2016: 17 · 2015: 12 · 2014: 25 · 2013: 25 · 2012: 15
FWCI
13.36
Type
journal article
Language
en
Update notices
correction (2008-11-13)
Open access
Licence
cc-by
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • SERVAL (Université de Lausanne) (publishedVersion, other-oa)
  • edoc (University of Basel) (acceptedVersion)
  • IRIS (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
Funders
  • University of Washington
  • Ministry of Education, Culture, Sports, Science and Technology
  • Bundesministerium für Bildung und Forschung
  • National Center for Geriatrics and Gerontology
Topics
  • Health Sciences › Nursing › Nutrition and Dietetics › Trace Elements in Health
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Connective tissue disorders research
  • Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
Keywords
zinc transporters, zinc metabolism, connective tissue formation, Ehlers-Danlos syndrome, BMP signaling, TGF-beta signaling, osteoblast maturation, chondrocyte maturation, odontoblasts, fibroblasts, loss-of-function mutations, animal models
MeSH terms
Adolescent, Amino Acid Sequence, Animals, Cells, Cultured, Connective Tissue, DNA Mutational Analysis, Ehlers-Danlos Syndrome, Humans, Models, Biological, Molecular Sequence Data, Morphogenesis, Osteogenesis, Pedigree, Zinc, Signal Transduction, Transforming Growth Factor beta, Sequence Homology, Amino Acid, Mice, Knockout, Bone Morphogenetic Proteins, Cation Transport Proteins, Mice, Young Adult

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