Abstract
Major histocompatibility complex class II plays a key role in the immune response, by presenting processed antigens to CD4+ lymphocytes. Major histocompatibility complex class II expression is controlled at the transcriptional level by at least four trans-acting genes: CIITA, RFXANK, RFX5 and RFXAP. Defects in these regulatory genes cause MHC class II immunodeficiency, which is frequent in North Africa. The aim of this study was to describe the immunological and molecular characteristics of ten unrelated Moroccan patients with MHC class II deficiency. Immunological examinations revealed a lack of expression of MHC class II molecules at the surface of peripheral blood mononuclear cells, low CD4+ T lymphocyte counts and variable serum immunoglobulin (IgG, IgM and IgA) levels. In addition, no MHC class II (HLA DR) expression was observed on lymphoblasts. The molecular analysis identified the same homozygous 752delG26 mutation in the RFXANK genes of all patients. This finding confirms the association between the high frequency of the combined immunodeficiency and the defect in MHC class II expression and provides strong evidence for a founder effect of the 752delG26 mutation in the North African population. These findings should facilitate the establishment of molecular diagnosis and improve genetic counselling for affected Moroccan families.
Similar content being viewed by others
References
Bejaoui M, Barbouche MR, Dellagi K (1997) Les déficits immunitaires primitifs en Tunisie; étude de 152 cas. Arch Pédiatr 4:827–831
Bejaoui M, Barbouche MR, Mellouli F et al (1998) Déficit immunitaire primitif par défaut d’expression des antigènes de classe II: neuf observations tunisiennes. Arch Pediatr 5:1089–1093
Benallegue M, Kedjif F (1984) Consanguinité et santé publique, étude algérienne. Arch Fr Pédiatr 41:435–440
Benichou B, Strominger JL (1991) Class II-antigen-negative patient and mutant B-cell lines represent at least three, and probably four, distint genetic defects defined by complementation analysis. Proc Natl Acad Sci USA 88:4285–4288
Bousfiha AA, Ailal F, Picard C et al (2008) Epidémiologie et classification des déficits immunitaires primitifs. Rev Mar Mal Enf 18:5–11
Cresswell P (1994) Assembly, transport and function of MHC class II molecules. Annu Rev Immunol 12:259–293
Durant B, Sperisen P, Emery P et al (1997) RFXAP, a novel subunit of the RFX DNA binding complex, is mutated in MHC class II deficiency. EMBO J 16:1045–1055
Geha RS, Notarangelo LD, Casanova JL et al (2007) International Union of Immunological Societies Primary Immunodeficiency Diseases Classification Committee. Primary immunodeficiency diseases: an update from the International Union of Immunological Societies Primary Immunodeficiency Diseases Classification Committee
Griscelli C (1991) Combined immunodeficiency with defective expression in MHC class II genes. Clin Immunol Immunopath 61:106–110
Griscelli C, Lisowska-Grospierre B, Le Deist F et al (1989) Combined immunodeficiency with abnormal expression of MHC class II genes. Clin Immunol Immunopathol 50:S140–S148
Griscelli C, Lisowska-Grospierre B, Mach B et al (1993) Combined immunodeficiency with defective expression in MHC class II genes. In: Rosen FS, Seligman M (eds) Immunodeficiencies. Harwood Academic, Chur, Switzerland, p 141
Hume CR, Lee JS (1989) Congenital immunodeficiency associated with absence of HLA class II antigens on lymphocyte result from distinct mutations in transacting factors. Hum Immunol 26:288–309
Klein C, Lisowska-Grospierre B, Ledeist F et al (1993) Major histocompatibility complex class II deficiency: clinical manifestations, immunological features and outcome. J Pediatr 123(6):921–928
Krawczyk M, Reith W (2006) Regulation of MHC class II expression, a unique regulatory system identified by the study of a primary immunodeficiency disease. Journal compilation 67:183–197
Lamdaouer Bouazzaoui N (1994) Consanguinité et Santé publique au Maroc. Bull Acad Natle Med 178:1013–1027
Lennon-Dumenil AM, Barbouche MR, Vedrenne J et al (2001) Uncoordinated HLA-D gene expression in a RFXANK-defective patient with MHC class II deficiency. J Immunol 166:5681–5687
Lisowska-Grospierre B, Fondaneche MC, Rols MP et al (1994) Two complementation groups accent for most cases of inherited MHC class II deficiency. Hum Mol Genet 3:953–958
Mach B, Steimle V, Martinez-Soria E, Reith W (1996) Regulation of MHC class genes: lessons from a disease. Annu Rev Immunol 10:153–331
Masternak K, Barras E, Zufferey M et al (1998) A gene encoding a novel RFX-associated transactivator is mutated in the majority of MHC class II deficiency patients. Nat Genet 20:273–277
Masternak K, Muhlethaler-Mottet A, Villard J et al (2000) CIITA is a transcriptional coactivator that is recruited to MHC II promoters by multiple synergistic interactions with an enhanceosome complex. Genes Dev 14:1156–1166
Nagarajan UM, Louis-Plence P, DeSandro A et al (1999) RFX-B is the gene responsible for the most common cause of the bare lymphocyte syndrome, an MHC class II immunodeficiency. Immunity 10:153–162
Nagarajan UM, Peijnenburg A, Gobin SJ et al (2000) Novel mutations within the RFX-B gene and partial rescue of MHC and related genes through exogenous class II transactivator in RFX-B-deficient cells. J Immunol 164:3666–3674
Nekrep N, Geyer M, Jabrane-Ferrat N, Peterlin BM (2001) Analysis of ankyrin repeats reveals how a single point mutation in RFXANK results in bare lymphocyte syndrome. Mol Cell Biol 21:5566–5576
Peijnenburg A, Van Eggermond MC, Van der Berg R et al (1999) Molecular analysis of an MHC class II deficiency patient reveals a novel mutation in the RFX5 gene. Immunogenetics 49:338–345
Reith W, Satola S, Sanchez CH et al (1988) Congenital immunodeficiency with a regulatory defect in MHC class II gene expression lacks a specific HLA-DR promoter binding protein, RF-X. Cell 53:897–906
Report of an IUIS Scientific Group (1999) Primary immunodeficiency diseases. Clin Exp Immunol 118(suppl 1):1–28
Saleem MA, Arkwright PD, Davies EG et al (2000) Clinical course of patients with major histocompatibility complex class II deficiency. Arch Dis Child 83:356–359
Shearer WT, Rosenblatt HM, Gelman RS et al (2003) Lymphocyte subsets in healthy children from birth through 18 years of age: the Pediatric AIDS Clinical Trials Group P1009 study. J Allergy Clin Immunol 112(5):973–980
Steimle V, Durant B, Barras E et al (1995) A novel DNA binding regulatory factor is mutated in primary MHC class II deficiency (bare lymphocyte syndrome). Genes Dev 9:1021–1032
Steimle V, Otten LA, Zufferey M, Mach B (1993) Complementation cloning of an MHC class II transactivator mutated in hereditary MHC class II deficiency (or bare lymphocyte syndrome). Cell 75:135–146
Steimle V, Siegrist CA, Mottet A et al (1994) Regulation of MHC class II expression by interferon mediated by the transactivator gene CIITA. Science 265:106–109
Villard J, Lisowska-Grospierre B, Van der Elsen P et al (1997) Mutation of RFXAP, a regulator MHC class II gene, in primary MHC class II deficiency. N Engl J Med 337:748–753
Ward AM (1998) Protein reference unit handbook of clinical immunochemistry, 2nd edn. PRU Publications, Sheffield
Wiszniewski W, Fondaneche MC, Lambert N et al (2000) Founder effect for a 26-bp deletion in the RFXANK gene in North African major histocompatibility complex class II-deficient patients belonging to complementation group B. Immunogenetics 51:261–267
Wiszniewski W, Fondaneche MC, Louise-Plence P et al (2003) Novel mutations in the RFXANK gene: RFX complex containing in vitro-generated RFXANK mutant binds the promoter without transactivating MHC II. Immunogenetics 54:747–755
Acknowledgements
We would particularly like to thank Dr Capucine Picard (Centre d’étude des déficits immunitaires. Hôpital Necker-Enfants Malades, Paris) and Professor Jean-Laurent Casanova (Rockefeller University, New York and Head of the Laboratory of Human Genetics of Infectious Diseases, INSERM-U550, Faculté Necker) for their help with the writing of this manuscript. We would also like to thank Dr EL Chadly (Cytogenetics Laboratory, Institut Pasteur du Maroc), Dr Omar Abidi (Genetics Laboratory, Institut Pasteur du Maroc) and Pr R. Barbouch (Immunology Laboratory, Institut Pasteur de la Tunisie).
The authors demonstrate to have had no financial relationship with the organisation that supported this research.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Naamane, H., El Maataoui, O., Ailal, F. et al. The 752delG26 mutation in the RFXANK gene associated with major histocompatibility complex class II deficiency: evidence for a founder effect in the Moroccan population. Eur J Pediatr 169, 1069–1074 (2010). https://doi.org/10.1007/s00431-010-1179-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00431-010-1179-6