Artemis splice defects cause atypical SCID and can be restored in... (2011)

Title Artemis splice defects cause atypical SCID and can be restored in vitro by an antisense oligonucleotide
Published in Genes and Immunity, Vol. 12, No. 6, p.434-444. ISSN 14664879.
Author H. IJspeert; A.C. Lankester; J.M. van den Berg; W. Wiegant; M.C. van Zelm; C.M.R. Weemaes; A. Warris; Q. Pan-Hammarstrom; A. Pastink; M.J.D. van Tol; J.J.M. van Dongen; D.C. van Gent; M. van der Burg
Degree grantor Universiteit van Amsterdam
Date 2011
Language English
Type Article
Abstract Artemis deficiency is known to result in classical T-B- severe combined immunodeficiency (SCID) in case of Artemis null mutations, or Omenn's syndrome in case of hypomorphic mutations in the Artemis gene. We describe two unrelated patients with a relatively mild clinical T-B- SCID phenotype, caused by different homozygous Artemis splice-site mutations. The splice-site mutations concern either dysfunction of a 5' splice-site or an intronic point mutation creating a novel 3' splice-site, resulting in mutated Artemis protein with residual activity or low levels of wild type (WT) Artemis transcripts. During the first 10 years of life, the patients suffered from recurrent infections necessitating antibiotic prophylaxis and intravenous immunoglobulins. Both mutations resulted in increased ionizing radiation sensitivity and insufficient variable, diversity and joining (V(D)J) recombination, causing B-lymphopenia and exhaustion of the naive T-cell compartment. The patient with the novel 30 splice-site had progressive granulomatous skin lesions, which disappeared after stem cell transplantation (SCT). We showed that an alternative approach to SCT can, in principle, be used in this case; an antisense oligonucleotide (AON) covering the intronic mutation restored WT Artemis transcript levels and non-homologous end-joining pathway activity in the patient fibroblasts. Genes and Immunity (2011) 12, 434-444; doi:10.1038/gene.2011.16; published online 10 March 2011
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Persistent Identifier urn:nbn:nl:ui:29-434822
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Source University of Amsterdam

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