Griscelli syndrome: Characterization of a new mutation and rescue of T-cytotoxic activity by retroviral transfer of RAB27A gene

Griscelli syndrome: Characterization of a new mutation and rescue of T-cytotoxic activity by retroviral transfer of RAB27A gene

Author Bizario, JCS Google Scholar
Feldmann, J. Google Scholar
Castro, F. A. Google Scholar
Menasche, G. Google Scholar
Jacob, CMA Google Scholar
Cristofani, L. Google Scholar
Casella, E. B. Google Scholar
Voltarelli, J. C. Google Scholar
De Saint-Basile, G. Google Scholar
Espreafico, E. M. Google Scholar
Institution Dept Biol Celular
Dept Mol & Bioagnetes Patogen
Universidade de São Paulo (USP)
Universidade Federal de São Paulo (UNIFESP)
Abstract Griscelli syndrome (GS) is caused by mutations in the MYO5A (GS1), RAB27A (GS2), or MLPH (GS3) genes, all of which lead to a similar pigmentary dilution. in addition, GS1 patients show primary neurological impairment, whereas GS2 patients present immunodeficiency and periods of lymphocyte proliferation and activation, leading to their infiltration in many organs, such as the nervous system, causing secondary neurological damage. We report the diagnosis of GS2 in a 4-year-old child with haemophagocytic syndrome, immunodeficiency, and secondary neurological disorders. Typical melanosome accumulation was found in skin melanocytes and pigment clumps were observed in hair shafts. Two heterozygous mutant alleles of the RAB27A gene were found, a C-T transition (C352T) that leads to Q118stop and a G-C transversion on the exon 5 splicing donor site (G467+1C). Functional assays showed increased cellular activation and decreased cytotoxic activity of NK and CD8+ T cells, associated with defective lytic granules release. Myosin-Va expression and localization in the patient lymphocytes were also analyzed. Most importantly, we show that cytotoxic activity of the patient's CD8+ T lymphocytes can be rescued in vitro by RAB27A gene transfer mediated by a recombinant retroviral vector, a first step towards a potential treatment of the acute phase of GS2 by RAB27A transduced lymphocytes.
Keywords immunodeficiency diseases
Griscelli syndrome
cell trafficking
gene therapy
Language English
Date 2004-07-01
Published in Journal of Clinical Immunology. New York: Kluwer Academic/plenum Publ, v. 24, n. 4, p. 397-410, 2004.
ISSN 0271-9142 (Sherpa/Romeo, impact factor)
Publisher Kluwer Academic/plenum Publ
Extent 397-410
Access rights Closed access
Type Article
Web of Science ID WOS:000221665700009

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