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Ott de Bruin, Lisa

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Ott de Bruin

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Lisa

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Ott de Bruin, Lisa
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    EXTL3 mutations cause skeletal dysplasia, immune deficiency, and developmental delay
    (The Rockefeller University Press, 2017) Volpi, Stefano; Yamazaki, Yasuhiro; Brauer, Patrick M.; van Rooijen, Ellen; Hayashida, Atsuko; Slavotinek, Anne; Sun Kuehn, Hye; Di Rocco, Maja; Rivolta, Carlo; Bortolomai, Ileana; Du, Likun; Felgentreff, Kerstin; Ott de Bruin, Lisa; Hayashida, Kazutaka; Freedman, George; Marcovecchio, Genni Enza; Capuder, Kelly; Rath, Prisni; Luche, Nicole; Hagedorn, Elliott; Buoncompagni, Antonella; Royer-Bertrand, Beryl; Giliani, Silvia; Poliani, Pietro Luigi; Imberti, Luisa; Dobbs, Kerry; Poulain, Fabienne E.; Martini, Alberto; Manis, John; Linhardt, Robert J.; Bosticardo, Marita; Rosenzweig, Sergio Damian; Lee, Hane; Puck, Jennifer M.; Zúñiga-Pflücker, Juan Carlos; Zon, Leonard; Park, Pyong; Superti-Furga, Andrea; Notarangelo, Luigi D.
    We studied three patients with severe skeletal dysplasia, T cell immunodeficiency, and developmental delay. Whole-exome sequencing revealed homozygous missense mutations affecting exostosin-like 3 (EXTL3), a glycosyltransferase involved in heparan sulfate (HS) biosynthesis. Patient-derived fibroblasts showed abnormal HS composition and altered fibroblast growth factor 2 signaling, which was rescued by overexpression of wild-type EXTL3 cDNA. Interleukin-2–mediated STAT5 phosphorylation in patients’ lymphocytes was markedly reduced. Interbreeding of the extl3-mutant zebrafish (box) with Tg(rag2:green fluorescent protein) transgenic zebrafish revealed defective thymopoiesis, which was rescued by injection of wild-type human EXTL3 RNA. Targeted differentiation of patient-derived induced pluripotent stem cells showed a reduced expansion of lymphohematopoietic progenitor cells and defects of thymic epithelial progenitor cell differentiation. These data identify EXTL3 mutations as a novel cause of severe immune deficiency with skeletal dysplasia and developmental delay and underline a crucial role of HS in thymopoiesis and skeletal and brain development.
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    Novel Genome-Editing Tools to Model and Correct Primary Immunodeficiencies
    (Frontiers Media S.A., 2015) Ott de Bruin, Lisa; Volpi, Stefano; Musunuru, Kiran
    Severe combined immunodeficiency (SCID) and other severe non-SCID primary immunodeficiencies (non-SCID PID) can be treated by allogeneic hematopoietic stem cell (HSC) transplantation, but when histocompatibility leukocyte antigen-matched donors are lacking, this can be a high-risk procedure. Correcting the patient’s own HSCs with gene therapy offers an attractive alternative. Gene therapies currently being used in clinical settings insert a functional copy of the entire gene by means of a viral vector. With this treatment, severe complications may result due to integration within oncogenes. A promising alternative is the use of endonucleases such as ZFNs, TALENs, and CRISPR/Cas9 to introduce a double-stranded break in the DNA and thus induce homology-directed repair. With these genome-editing tools a correct copy can be inserted in a precisely targeted “safe harbor.” They can also be used to correct pathogenic mutations in situ and to develop cellular or animal models needed to study the pathogenic effects of specific genetic defects found in immunodeficient patients. This review discusses the advantages and disadvantages of these endonucleases in gene correction and modeling with an emphasis on CRISPR/Cas9, which offers the most promise due to its efficacy and versatility.