title: Mutations in EXTL3 Cause Neuro-immuno-skeletal Dysplasia Syndrome.
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.
authors.affiliation: Department 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.
authors.forename: Machteld M
authors.initials: MM
authors.lastname: Oud
authors.affiliation: Department 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.
authors.forename: Paul
authors.initials: P
authors.lastname: Tuijnenburg
authors.affiliation: Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Maja
authors.initials: M
authors.lastname: Hempel
authors.affiliation: Laboratory Genetic Metabolic Diseases, Academic Medical Centre, PO Box 22660, 1100 DD Amsterdam, the Netherlands.
authors.forename: Naomi
authors.initials: N
authors.lastname: van Vlies
authors.affiliation: Department of Pathology, Academic Medical Center, University of Amsterdam, PO Box 22660, 1100 DD Amsterdam, the Netherlands.
authors.forename: Zemin
authors.initials: Z
authors.lastname: Ren
authors.affiliation: Laboratory Genetic Metabolic Diseases, Academic Medical Centre, PO Box 22660, 1100 DD Amsterdam, the Netherlands.
authors.forename: Sacha
authors.initials: S
authors.lastname: Ferdinandusse
authors.affiliation: Department 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.
authors.forename: Machiel H
authors.initials: MH
authors.lastname: Jansen
authors.affiliation: Department of Pediatrics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: René
authors.initials: R
authors.lastname: Santer
authors.affiliation: Department of Pediatrics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Jessika
authors.initials: J
authors.lastname: Johannsen
authors.affiliation: COSgene, Great Ormond Street Institute of Child Health, University College London, WC1N 1EH London, UK.
authors.forename: Chiara
authors.initials: C
authors.lastname: Bacchelli
authors.affiliation: Department of Clinical Genetics, Academic Medical Center, University of Amsterdam, PO Box 22660, 1100 DD Amsterdam, the Netherlands.
authors.forename: Marielle
authors.initials: M
authors.lastname: Alders
authors.affiliation: Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada; McGill University and Génome Québec Innovation Centre, Montreal, QC H3A 0G1, Canada.
authors.forename: Rui
authors.initials: R
authors.lastname: Li
authors.affiliation: COSgene, Great Ormond Street Institute of Child Health, University College London, WC1N 1EH London, UK.
authors.forename: Rosalind
authors.initials: R
authors.lastname: Davies
authors.affiliation: Division of Clinical and Metabolic Genetics, Department of Paediatrics, The Hospital for Sick Children and University of Toronto, Toronto, ON M5G 1X8, Canada.
authors.forename: Lucie
authors.initials: L
authors.lastname: Dupuis
authors.affiliation: Department of Immunology, Great Ormond Street Hospital, WC1N 3JH London, UK.
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Cale
authors.affiliation: Laboratory Genetic Metabolic Diseases, Academic Medical Centre, PO Box 22660, 1100 DD Amsterdam, the Netherlands.
authors.forename: Ronald J A
authors.initials: RJA
authors.lastname: Wanders
authors.affiliation: Department of Pathology, Academic Medical Center, University of Amsterdam, PO Box 22660, 1100 DD Amsterdam, the Netherlands.
authors.forename: Steven T
authors.initials: ST
authors.lastname: Pals
authors.affiliation: COSgene, Great Ormond Street Institute of Child Health, University College London, WC1N 1EH London, UK.
authors.forename: Louise
authors.initials: L
authors.lastname: Ocaka
authors.affiliation: COSgene, Great Ormond Street Institute of Child Health, University College London, WC1N 1EH London, UK.
authors.forename: Chela
authors.initials: C
authors.lastname: James
authors.affiliation: Division of Pediatric Stem Cell Transplantation and Immunology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Müller
authors.affiliation: Division of Pediatric Stem Cell Transplantation and Immunology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Kai
authors.initials: K
authors.lastname: Lehmberg
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Institute of Human Genetics, Technische Universität München, 81675 München, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Strom
authors.affiliation: Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Engels
authors.affiliation: COSgene, Great Ormond Street Institute of Child Health, University College London, WC1N 1EH London, UK.
authors.forename: Hywel J
authors.initials: HJ
authors.lastname: Williams
authors.affiliation: COSgene, Great Ormond Street Institute of Child Health, University College London, WC1N 1EH London, UK.
authors.forename: Phil
authors.initials: P
authors.lastname: Beales
authors.affiliation: Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, PO Box 9101, 6500 HB Nijmegen, the Netherlands.
authors.forename: Ronald
authors.initials: R
authors.lastname: Roepman
authors.affiliation: Serviςo de Genética, Departamento de Pediatria, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Centro Académico de Medicina de Lisboa, 1640-035 Lisboa, Portugal.
authors.forename: Patricia
authors.initials: P
authors.lastname: Dias
authors.affiliation: Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, PO Box 9101, 6500 HB Nijmegen, the Netherlands.
authors.forename: Han G
authors.initials: HG
authors.lastname: Brunner
authors.affiliation: Department 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.
authors.forename: Jan-Maarten
authors.initials: JM
authors.lastname: Cobben
authors.affiliation: Emerita, Department of Radiology, Great Ormond Street Hospital, WC1N 3JH London, UK.
authors.forename: Christine
authors.initials: C
authors.lastname: Hall
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 8 L1, Canada.
authors.forename: Taila
authors.initials: T
authors.lastname: Hartley
authors.affiliation: COSgene, Great Ormond Street Institute of Child Health, University College London, WC1N 1EH London, UK.
authors.forename: Polona
authors.initials: P
authors.lastname: Le Quesne Stabej
authors.affiliation: Division of Clinical and Metabolic Genetics, Department of Paediatrics, The Hospital for Sick Children and University of Toronto, Toronto, ON M5G 1X8, Canada.
authors.forename: Roberto
authors.initials: R
authors.lastname: Mendoza-Londono
authors.affiliation: COSgene, 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.
authors.forename: E Graham
authors.initials: EG
authors.lastname: Davies
authors.affiliation: COSgene, 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.
authors.forename: Sérgio B
authors.initials: SB
authors.lastname: de Sousa
authors.affiliation: Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Davor
authors.initials: D
authors.lastname: Lessel
authors.affiliation: Department 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.
authors.forename: Heleen H
authors.initials: HH
authors.lastname: Arts
authors.affiliation: Department of Experimental Immunology, Academic Medical Centre, PO Box 22660, 1100 DD Amsterdam, the Netherlands. Electronic address: t.w.kuijpers@amc.uva.nl.
authors.forename: Taco W
authors.initials: TW
authors.lastname: Kuijpers
mesh_terms: D000483:Alleles; D002460:Cell Line; D045744:Cell Line, Tumor; D002807:Chondroitin / Q000097:blood / Q000652:urine; D056915:DNA Copy Number Variations; D055106:Genome-Wide Association Study; D006025:Glycosaminoglycans / Q000378:metabolism; D006801:Humans; D009139:Musculoskeletal Abnormalities / Q000175:diagnosis / Q000235:genetics*; D020125:Mutation, Missense; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics*; D010009:Osteochondrodysplasias / Q000175:diagnosis / Q000235:genetics*; D016511:Severe Combined Immunodeficiency / Q000175:diagnosis / Q000235:genetics
chemical_list: C110774:EXTL3 protein, human; D006025:Glycosaminoglycans; D002807:Chondroitin; D017351:N-Acetylglucosaminyltransferases
keywords: EXTL3; T cell SCID; exostosin; heparan sulfate; neuro-immuno-skeletal dysplasia