Abstract
The Wiskott-Aldrich syndrome (WAS) is a primary immunodeficiency disease caused by mutations in the Wiskott-Aldrich Protein (WASP) gene, which typically leads to absent WASP protein expression in WAS leukocytes. However, some patients have been found with small populations of WASP-expressing cells caused by reverse or second-site mutations that allow protein expression. An international consortium was established to further investigate these phenomena. This paper summarizes data collected by this consortium that was presented at a workshop held during the XIIth Meeting of the European Society for Immunodeficiencies (ESID), October, 2006. WASP reversions were noted in approximately 11% of 272 patients tested. Many different cell lineages showed reversions. These data form the foundation for further investigation into this phenomenon, which has implications for therapy of this disease.
This is a preview of subscription content, log in via an institution to check access.
References
Ariga T, Kondoh T, Yamaguchi K, Yamada M, Sasaki S, Nelson DL, et al. Spontaneous in vivo reversion of an inherited mutation in the Wiskott-Aldrich syndrome. J Immunol 2001;166:5245–9.
Wada T, Konno A, Schurman SH, Garabedian EK, Anderson SM, Kirby M, et al. Second-site mutation in the Wiskott-Aldrich syndrome (WAS) protein gene causes somatic mosaicism in two WAS siblings. J Clin Invest 2003;111:1389–97.
Yamada M, Ohtsu M, Kobayashi I, Kawamura N, Kobayashi K, Ariga T, et al. Flow cytometric analysis of Wiskott-Aldrich syndrome (WAS) protein in lymphocytes from WAS patients and their familial carriers. Blood 1999;93:756–7.
Zhu Q, Zhang M, Blaese RM, Derry JM, Junker A, Francke U, et al. The Wiskott-Aldrich syndrome and X-linked congenital thrombocytopenia are caused by mutations of the same gene. Blood 1995;86:3797–804.
Wada T, Schurman SH, Otsu M, Garabedian EK, Ochs HD, Nelson DL, et al. Somatic mosaicism in Wiskott-Aldrich syndrome suggests in vivo reversion by a DNA slippage mechanism. Proc Natl Acad Sci U S A 2001;98:8697–702.
Jin Y, Mazza C, Christie JR, Giliani S, Fiorini M, Mella P, et al. Mutations of the Wiskott-Aldrich Syndrome Protein (WASP): hotspots, effect on transcription, and translation and phenotype/genotype correlation. Blood 2004;104:4010–9.
Lutskiy MI, Beardsley DS, Rosen FS, Remold-O’Donnell E. Mosaicism of NK cells in a patient with Wiskott-Aldrich syndrome. Blood 2005;106:2815–7.
Wada T, Schurman SH, Jagadeesh GJ, Garabedian EK, Nelson DL, Candotti F. Multiple patients with revertant mosaicism in a single Wiskott-Aldrich syndrome family. Blood 2004;104:1270–2.
Du W, Kumaki S, Uchiyama T, Yachie A, Yeng Looi C, Kawai S, et al. A second-site mutation in the initiation codon of WAS (WASP) results in expansion of subsets of lymphocytes in an Wiskott-Aldrich syndrome patient. Hum Mutat 2006;27:370–5.
Hirschhorn R, Yang DR, Puck JM, Huie ML, Jiang CK, Kurlandsky LE. Spontaneous in vivo reversion to normal of an inherited mutation in a patient with adenosine deaminase deficiency. Nat Genet 1996;13:290–5.
Stephan V, Wahn V, Le Deist F, Dirksen U, Broker B, Muller-Fleckenstein I, et al. Atypical X-linked severe combined immunodeficiency due to possible spontaneous reversion of the genetic defect in T cells. N Engl J Med 1996;335:1563–7.
Tone Y, Wada T, Shibata F, Toma T, Hashida Y, Kasahara Y, Koizumi S, et al. Somatic revertant mosaicism in a patient with leukocyte adhesion deficiency type 1. Blood 2007;109:1182–4.
Jain A, Ma CA, Liu S, Brown M, Cohen J, Strober W. Specific missense mutations in NEMO result in hyper-IgM syndrome with hypohydrotic ectodermal dysplasia. Nat Immunol 2001;2:223–8.
Nishikomori R, Akutagawa H, Maruyama K, Nakata-Hizume M, Ohmori K, Mizuno K, et al. X-linked ectodermal dysplasia and immunodeficiency caused by reversion mosaicism of NEMO reveals a critical role for NEMO in human T-cell development and/or survival. Blood 2004;103:4565–72.
Darling TN, Yee C, Bauer JW, Hintner H, Yancey KB. Revertant mosaicism: partial correction of a germ-line mutation in COL17A1 by a frame-restoring mutation. J Clin Invest 1999;103:1371–7.
Jonkman MF, Scheffer H, Stulp R, Pas HH, Nijenhuis M, Heeres K, et al. Revertant mosaicism in epidermolysis bullosa caused by mitotic gene conversion. Cell 1997;88:543–51.
Lo Ten Foe JR, Kwee ML, Rooimans MA, Oostra AB, Veerman AJ, van Weel M, et al. Somatic mosaicism in Fanconi anemia: molecular basis and clinical significance. Eur J Hum Genet 1997;5:137–48.
Waisfisz Q, Morgan NV, Savino M, de Winter JP, van Berkel CG, Hoatlin ME, et al. Spontaneous functional correction of homozygous fanconi anaemia alleles reveals novel mechanistic basis for reverse mosaicism. Nat Genet 1999;22:379–83.
Kvittingen EA, Rootwelt H, Berger R, Brandtzaeg P. Self-induced correction of the genetic defect in tyrosinemia type I. J Clin Invest 1994;94:1657–61.
Kvittingen EA, Rootwelt H, Brandtzaeg P, Bergan A, Berger R. Hereditary tyrosinemia type I. Self-induced correction of the fumarylacetoacetase defect. J Clin Invest 1993;91:1816–21.
Blaese RM, Culver KW, Miller AD, Carter CS, Fleisher T, Clerici M, et al. T lymphocyte-directed gene therapy for ADA- SCID: initial trial results after 4 years. Science 1995;270:475–80.
Cavazzana-Calvo M, Hacein-Bey S, de Saint Basile G, Gross F, Yvon E, Nusbaum P, et al. Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease. Science 2000;288:669–72.
Candotti F, Facchetti F, Blanzuoli L, Stewart DM, Nelson DL, Blaese RM. Retrovirus-mediated WASP gene transfer corrects defective actin polymerization in B cell lines from Wiskott-Aldrich syndrome patients carrying ’null’ mutations. Gene Ther 1999;6:1170–4.
Acknowledgments
The authors wish to thank all those participating in the Working Party. Listed below are the participating groups and investigators (e-mail addresses are provided for those groups submitting sequence data):
Metabolism Branch, NCI, NIH, Bethesda, MD, USA—Donn Stewart, David Nelson
Genetics and Molecular Biology Branch, NHGRI, NIH, Bethesda, MD, USA—Fabio Candotti, fabio@mail.nih.gov
Department of Pediatrics, Hokkaido U., Sapporo, JP—Tadashi Ariga, Masafumi Yamada, tada-ari@med.hokudai.ac.jp
Center for Blood Research, Boston, MA, USA—Eileen Remold-O’Donnell, remold@cbr.med.harvard.edu
Department of Pediatrics, U. of Brescia, Brescia, IT—Silvia Giliani, Cinzia Mazza, Evelina Mazzolari, Lucia D. Notarangelo, Luigi D. Notarangelo, luigi.notarangelo@childrens.harvard.edu
Hospital Nacional de Pediatria “Profesor Dr. Juan P. Garrahan”, Buenos Aires, AR—Jorge Rossi, jrossi@garrahan.gov.ar
Department of Pediatrics, Hannover Medical School, Hannover, DE—Kaan Boztug, Christoph Klein, christophklein2007@googlemail.com
Institute of Child Health, London, UK—Adrian Thrasher, a.thrasher@ich.ucl.ac.uk
TIGET, HSR, Milano, IT—Anna Villa, Marita Bosticardo, anna.villa@itb.cnr.it
Moscow, RU—Anna Shcherbina, shcher26@hotmail.com
Department of Pediatrics, U. of Washington, Seattle, WA, USA—Hans Ochs, Hans.Ochs@seattlechildrens.org
Department of Pediatrics, Tohoku University School of Medicine, Sendai, JP—Yoji Sasahara, Satoru Kumaki, Shigeru Tsuchiya, kumakis@idac.tohoku.ac.jp
Department of Pediatrics, U. Ulm, Ulm, DE—Klaus Schwarz, Wilhelm Friedrich
Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA—Alexandra Filipovich
Hopital Necker-Enfant Malades, Paris, FR—Capucine Picard
Department of Pediatrics, Kanazawa U., Kanazawa, JP—Tazio Wada
Department of Immunology, St Bartholomews and The Royal London School of Medicine and Dentistry, London, UK—Hiliary Longhurst
Department of Laboratory Medicine, Karolinska University Hospital in Huddinge, Stockholm, SE—Lennart Hammarstrom
Department of Hematology/Oncology Dr. von Haunersches Kinderspital, Munchen, DE—Michael Albert
Department of Allergy/Immunology, Rush U. Medical Center, Chicago, IL, USA—Anita Gewurz
Servicio de Immunologia, HHUU Virgen del Rocio, Sevilla, SP—Berta Sanchez
Immunology Unit, Hospital Vall d’Hebron, Barcelona, SP—Teresa Espanol
The Queen Silvia Children’s Hospital, Goteborg, SE—Anders Fasth
Department of Immunology, St Bartholomews and The Royal London School of Medicine and Dentistry, London, UK—Hiliary Longhurst
Pediatric Immunology, UMCU, Utrecht, NL—NM Wulffraat
Department of Clinical Immunology and Allerfology, St. Anne’s U. Hospital, Brno, CZ—Jiri Lizman
Department of Pediatrics, U. Tennessee, Memphis, TN, USA—M. E. Conley
Pediatric Allergy/Immunology Associates PA, Dallas, TX, USA—Richard Wasserman
Division of Clinical Immunology, Mount Sinai School of Medicine, New York, NY, USA—Charlotte Cunningham-Rundles
Department of Pediatrics, Uludag U. Medical Faculty, Bursa, TR—Sara Sebnem Kilic
Laboratory of Medical Investigation in Dermatology and Immunodeficiencies, U. Sao Paulo School of Medicine, Sao Paulo, BR—Dewton de Morales Vasconcelos
Developmental Medicine Unit, School of Medicine U. of Wales, Swansea, UK—Gareth Morgan
Histocompatibility Laboratory, Children’s Memorial Health Institute, Warsaw, PL—Barbara Piatosa
Department of Immunology and Pediatric Rheumatology, Hospital Nacional de Ninos “Dr. Carlos Saenz Herrera”, San Jose, CR—Oscar Porras
Department of Pediatrics, U. of Milan, Milano, IT—Rosa Maria Dellepiane
Diskapi Children’s Hospital, Ankara, TR—Ayse Metin
Pediatric Department, C.H.C Espérance Montegnée (Liège), BE—Pierre Philippet
Department of Pediatrics, U. Bari, Bari, IT—Martire Baldassarre
Pediatric Immunology Laboratory, Hacettepe U., Children’s Hospital, Ankara, TR —Ozden Sanal
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Stewart, D.M., Candotti, F. & Nelson, D.L. The Phenomenon of Spontaneous Genetic Reversions in the Wiskott-Aldrich Syndrome: A Report of the Workshop of the ESID Genetics Working Party at the XIIth Meeting of the European Society for Immunodeficiencies (ESID). Budapest, Hungary October 4–7, 2006. J Clin Immunol 27, 634–639 (2007). https://doi.org/10.1007/s10875-007-9121-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10875-007-9121-z