Mutations in EXTL3 Cause Neuro-immuno-skeletal Dysplasia Syndrome

doi:10.1016/j.ajhg.2017.01.013

. 2017 Feb 2;100(2):281-296.

doi: 10.1016/j.ajhg.2017.01.013. Epub 2017 Jan 26.

Mutations in EXTL3 Cause Neuro-immuno-skeletal Dysplasia Syndrome

Machteld M Oud¹, Paul Tuijnenburg², Maja Hempel³, Naomi van Vlies⁴, Zemin Ren⁵, Sacha Ferdinandusse⁴, Machiel H Jansen², René Santer⁶, Jessika Johannsen⁶, Chiara Bacchelli⁷, Marielle Alders⁸, Rui Li⁹, Rosalind Davies⁷, Lucie Dupuis¹⁰, Catherine M Cale¹¹, Ronald J A Wanders⁴, Steven T Pals⁵, Louise Ocaka⁷, Chela James⁷, Ingo Müller¹², Kai Lehmberg¹², Tim Strom¹³, Hartmut Engels¹⁴, Hywel J Williams⁷, Phil Beales⁷, Ronald Roepman¹⁵, Patricia Dias¹⁶, Han G Brunner¹⁵, Jan-Maarten Cobben¹⁷, Christine Hall¹⁸, Taila Hartley¹⁹, Polona Le Quesne Stabej⁷, Roberto Mendoza-Londono¹⁰, E Graham Davies²⁰, Sérgio B de Sousa²¹, Davor Lessel³, Heleen H Arts²², Taco W Kuijpers²³

Affiliations

¹ 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.
² 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.
³ Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
⁴ Laboratory Genetic Metabolic Diseases, Academic Medical Centre, PO Box 22660, 1100 DD Amsterdam, the Netherlands.
⁵ Department of Pathology, Academic Medical Center, University of Amsterdam, PO Box 22660, 1100 DD Amsterdam, the Netherlands.
⁶ Department of Pediatrics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
⁷ COSgene, Great Ormond Street Institute of Child Health, University College London, WC1N 1EH London, UK.
⁸ Department of Clinical Genetics, Academic Medical Center, University of Amsterdam, PO Box 22660, 1100 DD Amsterdam, the Netherlands.
⁹ Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada; McGill University and Génome Québec Innovation Centre, Montreal, QC H3A 0G1, Canada.
¹⁰ Division of Clinical and Metabolic Genetics, Department of Paediatrics, The Hospital for Sick Children and University of Toronto, Toronto, ON M5G 1X8, Canada.
¹¹ Department of Immunology, Great Ormond Street Hospital, WC1N 3JH London, UK.
¹² Division of Pediatric Stem Cell Transplantation and Immunology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
¹³ Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Institute of Human Genetics, Technische Universität München, 81675 München, Germany.
¹⁴ Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany.
¹⁵ Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, PO Box 9101, 6500 HB Nijmegen, the Netherlands.
¹⁶ Serviςo de Genética, Departamento de Pediatria, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Centro Académico de Medicina de Lisboa, 1640-035 Lisboa, Portugal.
¹⁷ 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.
¹⁸ Emerita, Department of Radiology, Great Ormond Street Hospital, WC1N 3JH London, UK.
¹⁹ Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 8 L1, Canada.
²⁰ 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.
²¹ 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.
²² 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.
²³ Department of Experimental Immunology, Academic Medical Centre, PO Box 22660, 1100 DD Amsterdam, the Netherlands. Electronic address: t.w.kuijpers@amc.uva.nl.

PMID: 28132690
PMCID: PMC5294674
DOI: 10.1016/j.ajhg.2017.01.013

Mutations in EXTL3 Cause Neuro-immuno-skeletal Dysplasia Syndrome

Machteld M Oud et al. Am J Hum Genet. 2017.

. 2017 Feb 2;100(2):281-296.

doi: 10.1016/j.ajhg.2017.01.013. Epub 2017 Jan 26.

Authors

Affiliations

¹ 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.
² 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.
³ Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
⁴ Laboratory Genetic Metabolic Diseases, Academic Medical Centre, PO Box 22660, 1100 DD Amsterdam, the Netherlands.
⁵ Department of Pathology, Academic Medical Center, University of Amsterdam, PO Box 22660, 1100 DD Amsterdam, the Netherlands.
⁶ Department of Pediatrics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
⁷ COSgene, Great Ormond Street Institute of Child Health, University College London, WC1N 1EH London, UK.
⁸ Department of Clinical Genetics, Academic Medical Center, University of Amsterdam, PO Box 22660, 1100 DD Amsterdam, the Netherlands.
⁹ Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada; McGill University and Génome Québec Innovation Centre, Montreal, QC H3A 0G1, Canada.
¹⁰ Division of Clinical and Metabolic Genetics, Department of Paediatrics, The Hospital for Sick Children and University of Toronto, Toronto, ON M5G 1X8, Canada.
¹¹ Department of Immunology, Great Ormond Street Hospital, WC1N 3JH London, UK.
¹² Division of Pediatric Stem Cell Transplantation and Immunology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
¹³ Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Institute of Human Genetics, Technische Universität München, 81675 München, Germany.
¹⁴ Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany.
¹⁵ Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Centre, PO Box 9101, 6500 HB Nijmegen, the Netherlands.
¹⁶ Serviςo de Genética, Departamento de Pediatria, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Centro Académico de Medicina de Lisboa, 1640-035 Lisboa, Portugal.
¹⁷ 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.
¹⁸ Emerita, Department of Radiology, Great Ormond Street Hospital, WC1N 3JH London, UK.
¹⁹ Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 8 L1, Canada.
²⁰ 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.
²¹ 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.
²² 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.
²³ Department of Experimental Immunology, Academic Medical Centre, PO Box 22660, 1100 DD Amsterdam, the Netherlands. Electronic address: t.w.kuijpers@amc.uva.nl.

PMID: 28132690
PMCID: PMC5294674
DOI: 10.1016/j.ajhg.2017.01.013

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.

Keywords: EXTL3; T cell SCID; exostosin; heparan sulfate; neuro-immuno-skeletal dysplasia.

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Figures

**Figure 1**
Clinical Features of the Skeleton of Families A–E (A) Lateral spine radiographs arranged chronologically. Most affected individuals show severe platyspondyly (red boxes) with progressively severe kyphosis with increasing age (visualized for C:II-1, D:III-1, and D:IV-1); however, the affected siblings of family B do not (green boxes). Affected individual C:II-1 shows an additional abnormality of absent ossification of the anterior parts of the vertebral bodies in the upper lumbar region. Furthermore, wide intervertebral spaces are visible, and the vertebral bodies show some posterior constriction giving a pear shape. (B) Hand radiographs arranged chronologically. Up to the age of about 6 years, there is a delay in carpal bone ossification. The first metacarpals (arrowheads) and the second middle phalanges (broad arrows) are short. The fifth middle phalanges are short or absent in A:II-1, E:II-1, and E:II-2 (newborns). Affected individual B:II-2 has soft tissue preaxial polydactyly. (C) The pelvic radiographs show a variable degree of sloping acetabula with shallow lateral notches, coxa valga, and small capital femoral epiphyses. Elbow radiographs show dislocated radial heads with dysplastic radial heads.

**Figure 2**
Four Homozygous Missense Mutations in *EXTL3* in Five Unrelated Families (A) Pedigrees of five affected families. All affected individuals carry homozygous missense mutations in *EXTL3* (GenBank: NM_001440.3). In family A, II-1 is homozygous for c.1537C>T (M1). In family B, II-1 and II-2 are homozygous for c.2008T>G (M2). In families C and D, c.1382C>T segregates with disease. In family E, c.1970A>G (M4) segregates with disease. (B) Schematic overview of *EXTL3* and the corresponding protein (GenBank: NP_001431) shows the position of the missense mutations and protein changes. All four mutations are in exon 3. EXTL3 consists of two annotated domains: a transmembrane domain (amino acids 29–51) and a coiled-coil domain (amino acids 86–148). In addition, there are two predicted Pfam domains: a conserved EXT domain (amino acids 190–500) and a glycosyl transferase family 64 domain (amino acids 663–904) conserved between enzymes that catalyze the transfer reaction of N-acetylglucosamine and N-acetylgalactosamine.

**Figure 3**
EXTL3 Levels in T and B Lymphocyte Cell Lines (A) EXTL3 was absent in all B cell lymphoma cells, myeloid cells, or circulating B and T lymphocyte cell lines. However, strong T cell stimulation seemed to induce low levels of EXTL3. (B) Purified CD34⁺ hematopoietic stem cells and thymocyte cells were positive for EXTL3. This was true for early double-negative, double-positive, and late single-positive thymocyte cells. (C) Immunohistochemistry staining of normal neonate tissue for localization of EXTL3 shows moderate localization throughout the thymus. (D) Validation of EXTL3 antibody. The EXTL3 antibody shows a band for cells transfected with sgRNAs 1 and 2 and the empty vector, indicating the presence of EXTL3 in the cell lysate. Upon transfection with sgRNA 3, an EXTL3 knockout cell line was obtained; no band was visible, indicating the specificity of the antibody.

**Figure 4**
Immunophenotype and In Vitro Proliferation, Plasmablast Formation, and Immunoglobulin Production Data are shown for individuals A:II-1, B:II-1, and B:II-2 and a healthy adult control individual. (A) T cell subsets gated on CD3⁺CD4⁺ or CD3⁺CD8⁺ lymphocytes and B cell subsets gated on CD19⁺CD20⁺ lymphocytes. Numbers indicate percentages in the corresponding gates. (B) CFSE-labeled PBMCs were cultured with either medium or CpG and IL-2 and were gated on CD19⁺CD20^+/- lymphocytes. Gates were set for either CD27^bright (left) or CFSE^+/- and CD38^+/- (right) B cells for analysis of cell division and plasmablast formation. (C) CFSE-labeled PBMCs were cultured with either medium or anti-CD3 and anti-CD28 and were gated on CD3⁺CD4⁺ or CD3⁺CD8⁺ T lymphocytes and CD19⁺CD20^+/- B lymphocytes for analysis of direct (T cell) or indirect (B cell) proliferation upon TCR stimulation. ND means not determined. (D and E) Levels of IgG and IgM were determined by ELISA in the supernatants after 6 days of culture with medium, CpG and IL-2, or a combination of anti-IgM, anti-CD40, and IL-21. Error bars indicate SEM (n = 3).

**Figure 5**
Localization of EXTL3 to the Golgi Complex Is Lost in p.Arg513Cys Mutated Cells The localization of EXTL3 in fibroblasts derived from affected individuals is compared with that of two healthy control individuals. The cells were stained for EXTL3 (green), Golgi marker GM130 (red), and DAPI for the cell nucleus (blue). The localization of EXTL3 to the Golgi complex seen in control fibroblasts was lost in cells derived from affected individual A:II-1, but not in fibroblast cell lines from affected siblings B:II-1 and B:II-2. Scale bars represent 10 μm.

**Figure 6**
Mutations in *EXTL3* Affect Glycosaminoglycan Concentrations GAG concentrations in urine, serum, and fibroblasts from affected individuals and age-matched control samples. Concentrations of D0A0 for heparan sulfate (HS), D0a4 for dermatan sulfate (DS), and D0a6 (sulfated) and D0a0 (non-sulfated) for chondroitin sulfate (CS) are shown. Error bars indicate SD. (A) GAG concentrations in fibroblasts. HS concentrations were reduced in fibroblasts from all affected individuals except C:II-1. DS concentrations were within the normal range for the affected family members of family B and D:IV-1, increased in C:II-1, and reduced in A:II-1 and E:II-1. (B) GAG concentration in the serum from affected individuals and both parents of family B. HS concentrations were normal in affected individual A:II-1 and in both parents of family B (B:I-1 and B:I-2) but were decreased in the siblings of family B (B:II-1 and B:II-2). DS concentrations were elevated in all affected family members of families A and B, as well as in parent B:I-1. The non-sulfated CS concentration was elevated in individuals B:II-1 and B:II-2, and the sulfated CS concentration was markedly increased in B:II-2. (C) GAG concentrations in urine. HS concentrations for A:II-1 were normal but were decreased in both B:II-1 and B:II-2. DS was elevated in all three affected individuals. The non-sulfated CS concentration was elevated in all affected individuals, whereas D0a6 was elevated only in B:II-2.

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References

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1. Picard C., Al-Herz W., Bousfiha A., Casanova J.L., Chatila T., Conley M.E., Cunningham-Rundles C., Etzioni A., Holland S.M., Klein C. Primary Immunodeficiency Diseases: an Update on the Classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency 2015. J. Clin. Immunol. 2015;35:696–726. - PMC - PubMed
1. Warman M.L., Cormier-Daire V., Hall C., Krakow D., Lachman R., LeMerrer M., Mortier G., Mundlos S., Nishimura G., Rimoin D.L. Nosology and classification of genetic skeletal disorders: 2010 revision. Am. J. Med. Genet. A. 2011;155A:943–968. - PMC - PubMed
1. Ridanpää M., van Eenennaam H., Pelin K., Chadwick R., Johnson C., Yuan B., vanVenrooij W., Pruijn G., Salmela R., Rockas S. Mutations in the RNA component of RNase MRP cause a pleiotropic human disease, cartilage-hair hypoplasia. Cell. 2001;104:195–203. - PubMed
1. Boerkoel C.F., Takashima H., John J., Yan J., Stankiewicz P., Rosenbarker L., André J.L., Bogdanovic R., Burguet A., Cockfield S. Mutant chromatin remodeling protein SMARCAL1 causes Schimke immuno-osseous dysplasia. Nat. Genet. 2002;30:215–220. - PubMed

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[1] Bousfiha A., Jeddane L., Al-Herz W., Ailal F., Casanova J.L., Chatila T., Conley M.E., Cunningham-Rundles C., Etzioni A., Franco J.L. The 2015 IUIS Phenotypic Classification for Primary Immunodeficiencies. J. Clin. Immunol. 2015;35:727–738. - PMC - PubMed

[2] Bousfiha A., Jeddane L., Al-Herz W., Ailal F., Casanova J.L., Chatila T., Conley M.E., Cunningham-Rundles C., Etzioni A., Franco J.L. The 2015 IUIS Phenotypic Classification for Primary Immunodeficiencies. J. Clin. Immunol. 2015;35:727–738. - PMC - PubMed

[3] Picard C., Al-Herz W., Bousfiha A., Casanova J.L., Chatila T., Conley M.E., Cunningham-Rundles C., Etzioni A., Holland S.M., Klein C. Primary Immunodeficiency Diseases: an Update on the Classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency 2015. J. Clin. Immunol. 2015;35:696–726. - PMC - PubMed

[4] Picard C., Al-Herz W., Bousfiha A., Casanova J.L., Chatila T., Conley M.E., Cunningham-Rundles C., Etzioni A., Holland S.M., Klein C. Primary Immunodeficiency Diseases: an Update on the Classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency 2015. J. Clin. Immunol. 2015;35:696–726. - PMC - PubMed

[5] Warman M.L., Cormier-Daire V., Hall C., Krakow D., Lachman R., LeMerrer M., Mortier G., Mundlos S., Nishimura G., Rimoin D.L. Nosology and classification of genetic skeletal disorders: 2010 revision. Am. J. Med. Genet. A. 2011;155A:943–968. - PMC - PubMed

[6] Warman M.L., Cormier-Daire V., Hall C., Krakow D., Lachman R., LeMerrer M., Mortier G., Mundlos S., Nishimura G., Rimoin D.L. Nosology and classification of genetic skeletal disorders: 2010 revision. Am. J. Med. Genet. A. 2011;155A:943–968. - PMC - PubMed

[7] Ridanpää M., van Eenennaam H., Pelin K., Chadwick R., Johnson C., Yuan B., vanVenrooij W., Pruijn G., Salmela R., Rockas S. Mutations in the RNA component of RNase MRP cause a pleiotropic human disease, cartilage-hair hypoplasia. Cell. 2001;104:195–203. - PubMed

[8] Ridanpää M., van Eenennaam H., Pelin K., Chadwick R., Johnson C., Yuan B., vanVenrooij W., Pruijn G., Salmela R., Rockas S. Mutations in the RNA component of RNase MRP cause a pleiotropic human disease, cartilage-hair hypoplasia. Cell. 2001;104:195–203. - PubMed

[9] Boerkoel C.F., Takashima H., John J., Yan J., Stankiewicz P., Rosenbarker L., André J.L., Bogdanovic R., Burguet A., Cockfield S. Mutant chromatin remodeling protein SMARCAL1 causes Schimke immuno-osseous dysplasia. Nat. Genet. 2002;30:215–220. - PubMed

[10] Boerkoel C.F., Takashima H., John J., Yan J., Stankiewicz P., Rosenbarker L., André J.L., Bogdanovic R., Burguet A., Cockfield S. Mutant chromatin remodeling protein SMARCAL1 causes Schimke immuno-osseous dysplasia. Nat. Genet. 2002;30:215–220. - PubMed

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Mutations in EXTL3 Cause Neuro-immuno-skeletal Dysplasia Syndrome

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Mutations in EXTL3 Cause Neuro-immuno-skeletal Dysplasia Syndrome

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