Evidence map›Paper›PMID 28132690›Full record

ArticleAmerican journal of human genetics2017

Mutations in EXTL3 Cause Neuro-immuno-skeletal Dysplasia Syndrome.

Machteld M Oud, Paul Tuijnenburg, Maja Hempel, Naomi van Vlies, Zemin Ren, Sacha Ferdinandusse, Machiel H Jansen, René Santer, Jessika Johannsen, Chiara Bacchelli and 28 more

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in American journal of human genetics, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.

0numbers the graph read from it
0cells of the map it votes in
35citing papers in PubMed
3.6field-weighted citation impact, top 6% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

35 citing papers in PubMed, 101 citations in OpenAlex.

  1. Article
  2. Article
  3. Thymic inborn errors of immunity.The Journal of allergy and clinical immunology · 2025
    Review
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  5. Article
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  8. Article
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  11. Inborn errors of immunity associated with defects of thymic development.Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology · 2022
    Review
  12. Article
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  16. Article
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

38 authors at 15 institutions in 5 countries.

Machteld M OudDepartment of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, PO Box 9101, 6500 HB Nijmegen, the Netherlands. Electronic address: machteld.oud@radboudumc.nl.
Paul TuijnenburgDepartment of Experimental Immunology, Academic Medical Centre, PO Box 22660, 1100 DD Amsterdam, the Netherlands; Department of Pediatric Hematology, Immunology, and Infectious disease, Academic Medical Centre, PO Box 22660, 1100 DD Amsterdam, the Netherlands.
Maja HempelInstitute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
Naomi van VliesLaboratory Genetic Metabolic Diseases, Academic Medical Centre, PO Box 22660, 1100 DD Amsterdam, the Netherlands.
Zemin RenDepartment of Pathology, Academic Medical Center, University of Amsterdam, PO Box 22660, 1100 DD Amsterdam, the Netherlands.
Sacha FerdinandusseLaboratory Genetic Metabolic Diseases, Academic Medical Centre, PO Box 22660, 1100 DD Amsterdam, the Netherlands.
Machiel H JansenDepartment of Experimental Immunology, Academic Medical Centre, PO Box 22660, 1100 DD Amsterdam, the Netherlands; Department of Pediatric Hematology, Immunology, and Infectious disease, Academic Medical Centre, PO Box 22660, 1100 DD Amsterdam, the Netherlands.
René SanterDepartment of Pediatrics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
Jessika JohannsenDepartment of Pediatrics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
Chiara BacchelliCOSgene, Great Ormond Street Institute of Child Health, University College London, WC1N 1EH London, UK.
Marielle AldersDepartment of Clinical Genetics, Academic Medical Center, University of Amsterdam, PO Box 22660, 1100 DD Amsterdam, the Netherlands.
Rui LiDepartment of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada; McGill University and Génome Québec Innovation Centre, Montreal, QC H3A 0G1, Canada.
Rosalind DaviesCOSgene, Great Ormond Street Institute of Child Health, University College London, WC1N 1EH London, UK.
Lucie DupuisDivision of Clinical and Metabolic Genetics, Department of Paediatrics, The Hospital for Sick Children and University of Toronto, Toronto, ON M5G 1X8, Canada.
Catherine M CaleDepartment of Immunology, Great Ormond Street Hospital, WC1N 3JH London, UK.
Ronald J A WandersLaboratory Genetic Metabolic Diseases, Academic Medical Centre, PO Box 22660, 1100 DD Amsterdam, the Netherlands.
Steven T PalsDepartment of Pathology, Academic Medical Center, University of Amsterdam, PO Box 22660, 1100 DD Amsterdam, the Netherlands.
Louise OcakaCOSgene, Great Ormond Street Institute of Child Health, University College London, WC1N 1EH London, UK.
Chela JamesCOSgene, Great Ormond Street Institute of Child Health, University College London, WC1N 1EH London, UK.
Ingo MüllerDivision of Pediatric Stem Cell Transplantation and Immunology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
Kai LehmbergDivision of Pediatric Stem Cell Transplantation and Immunology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
Tim StromInstitute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Institute of Human Genetics, Technische Universität München, 81675 München, Germany.
Hartmut EngelsInstitute of Human Genetics, University of Bonn, 53127 Bonn, Germany.
Hywel J WilliamsCOSgene, Great Ormond Street Institute of Child Health, University College London, WC1N 1EH London, UK.
Phil BealesCOSgene, Great Ormond Street Institute of Child Health, University College London, WC1N 1EH London, UK.
Ronald RoepmanDepartment of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, PO Box 9101, 6500 HB Nijmegen, the Netherlands.
Patricia DiasServiςo de Genética, Departamento de Pediatria, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Centro Académico de Medicina de Lisboa, 1640-035 Lisboa, Portugal.
Han G BrunnerDepartment of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, PO Box 9101, 6500 HB Nijmegen, the Netherlands.
Jan-Maarten CobbenDepartment of Pediatrics, Academic Medical Center University Hospital, PO Box 22660, 1100 DD Amsterdam, the Netherlands; Department of Clinical Genetics, St. George's University Hospital, SW19 0ER London, UK.
Christine HallEmerita, Department of Radiology, Great Ormond Street Hospital, WC1N 3JH London, UK.
Taila HartleyChildren's Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 8 L1, Canada.
Polona Le Quesne StabejCOSgene, Great Ormond Street Institute of Child Health, University College London, WC1N 1EH London, UK.
Roberto Mendoza-LondonoDivision of Clinical and Metabolic Genetics, Department of Paediatrics, The Hospital for Sick Children and University of Toronto, Toronto, ON M5G 1X8, Canada.
E Graham DaviesCOSgene, Great Ormond Street Institute of Child Health, University College London, WC1N 1EH London, UK; Department of Immunology, Great Ormond Street Hospital, WC1N 3JH London, UK.
Sérgio B de SousaCOSgene, Great Ormond Street Institute of Child Health, University College London, WC1N 1EH London, UK; Medical Genetics Unit, Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra, 3000-602 Coimbra, Portugal; Faculty of Health Sciences, University of Beira Interior, 6200-506 Covilhã, Portugal.
Davor LesselInstitute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
Heleen H ArtsDepartment of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, PO Box 9101, 6500 HB Nijmegen, the Netherlands; Department of Pathology and Molecular Medicine, McMaster University Medical Centre, Hamilton, ON L8S 4J9, Canada.
Taco W KuijpersDepartment of Experimental Immunology, Academic Medical Centre, PO Box 22660, 1100 DD Amsterdam, the Netherlands. Electronic address: t.w.kuijpers@amc.uva.nl.
University College London · GBAcademic Medical Center · NLRadboud Institute for Molecular Life Sciences · NLUniversität Hamburg · DEUniversity Medical Center Hamburg-Eppendorf · DEChildren's Hospital of Eastern Ontario · CAGreat Ormond Street Hospital · GBHelmholtz Zentrum München · DEHospital de Santa Maria · PTHospital for Sick Children · CAMcGill University and Génome Québec Innovation Centre · CARadboud University Medical Center · NLUniversity of Amsterdam · NLUniversity of Bonn · DEUniversity of Toronto · CA

Funding

Medical Research Council G0801843
6 · The paper itself

Abstract

EXTL3 regulates the biosynthesis of heparan sulfate (HS), important for both skeletal development and hematopoiesis, through the formation of HS proteoglycans (HSPGs). By whole-exome sequencing, we identified homozygous missense mutations c.1382C>T, c.1537C>T, c.1970A>G, and c.2008T>G in EXTL3 in nine affected individuals from five unrelated families. Notably, we found the identical homozygous missense mutation c.1382C>T (p.Pro461Leu) in four affected individuals from two unrelated families. Affected individuals presented with variable skeletal abnormalities and neurodevelopmental defects. Severe combined immunodeficiency (SCID) with a complete absence of T cells was observed in three families. EXTL3 was most abundant in hematopoietic stem cells and early progenitor T cells, which is in line with a SCID phenotype at the level of early T cell development in the thymus. To provide further support for the hypothesis that mutations in EXTL3 cause a neuro-immuno-skeletal dysplasia syndrome, and to gain insight into the pathogenesis of the disorder, we analyzed the localization of EXTL3 in fibroblasts derived from affected individuals and determined glycosaminoglycan concentrations in these cells as well as in urine and blood. We observed abnormal glycosaminoglycan concentrations and increased concentrations of the non-sulfated chondroitin disaccharide D0a0 and the disaccharide D0a4 in serum and urine of all analyzed affected individuals. In summary, we show that biallelic mutations in EXTL3 disturb glycosaminoglycan synthesis and thus lead to a recognizable syndrome characterized by variable expression of skeletal, neurological, and immunological abnormalities.

Indexed as

AllelesCell LineCell Line, TumorChondroitinDNA Copy Number VariationsGenome-Wide Association StudyGlycosaminoglycansHumansMusculoskeletal AbnormalitiesMutation, MissenseN-AcetylglucosaminyltransferasesOsteochondrodysplasiasSevere Combined ImmunodeficiencyChondroitinEXTL3 protein, humanGlycosaminoglycansN-AcetylglucosaminyltransferasesexostosinEXTL3heparan sulfateneuro-immuno-skeletal dysplasiaT cell SCID

Identifiers

PMID28132690
PMCPMC5294674
OpenAlexW2582755256

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.