Whole-exome sequencing identifies Coronin-1A deficiency in 3 siblings with immunodeficiency and EBV-associated B-cell lymphoproliferation - 30/05/13
, Emmanuel Martin, PhD a, b, ∗, Wassila Carpentier, PhD d, Annick Lim, PhD e, Isabelle Callebaut, PhD f, Danielle Canioni, MD, PhD g, Fabian Hauck, MD a, b, Jacek Majewski, PhD h, i, Jeremy Schwartzentruber, MSc h, Patrick Nitschke, PhD j, Nicolas Sirvent, MD, PhD k, Pierre Frange, MD b, c, Capucine Picard, MD, PhD b, c, l, m, Stéphane Blanche, MD b, c, Patrick Revy, PhD a, b, Alain Fischer, MD, PhD a, b, c, Sylvain Latour, PhD a, b, ∗, Nada Jabado, MD, PhD h, i, n, ∗, Jean-Pierre de Villartay, PhD a, b, cAbstract |
Background |
Primary immunodeficiencies are a rare group of inborn diseases characterized by a broad clinical and genetic heterogeneity. Substantial advances in the identification of the underlying molecular mechanisms can be achieved through the study of patients with increased susceptibility to specific infections and immune dysregulation. We evaluated 3 siblings from a consanguineous family presenting with EBV-associated B-cell lymphoproliferation at an early age (12, 7½, and 14 months, respectively) and profound naive T-cell lymphopenia.
Objective |
On the basis of the hypothesis of a rare inborn immunodeficiency of autosomal recessive inheritance, we sought to characterize the underlying genetic defect.
Methods |
We performed genome-wide homozygosity mapping, followed by whole-exome sequencing.
Results |
We identified a homozygous inherited missense mutation in the gene encoding Coronin-1A (CORO1A) in the 3 siblings. This mutation, p. V134M, results in the substitution of an evolutionarily conserved amino acid within the β-propeller domain, which abrogates almost completely the protein expression in the patients' cells. In addition to a significant diminution of naive T-cell numbers, we found impaired development of a diverse T-cell repertoire, near-to-absent invariant natural killer T cells, and severely diminished mucosal-associated invariant T cell numbers.
Conclusions |
Our findings define a new clinical entity of a primary immunodeficiency with increased susceptibility to EBV-induced lymphoproliferation in patients associated with hypomorphic Coronin-1A mutation.
Le texte complet de cet article est disponible en PDF.Key words : Primary immunodeficiency, T-cell immunodeficiency, severe combined immune deficiency, EBV-associated B-cell lymphoproliferation, thymus, invariant natural killer T cell, mucosal-associated invariant T cell
Abbreviations used : EBER, ERK, FACS, GAPDH, GWHM, HSCT, iNKT, ITK, MAIT, PBL, SCID, TCR, WES
Plan
| Supported by institutional grants from INSERM, by the “Robert A Good/Jeffrey Modell Fellowship in Transplantation and Immunodeficiency” to D.M., and by grants from La Ligue Nationale contre le Cancer (Equipe Labellisée La Ligue; to J.-P.V.) and ERC PID-IMMUN (no. 249816; to A.F.). |
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| Disclosure of potential conflict of interest: D. Moshous has received research support from the Robert A Good/Jeffrey Modell Fellowship in Transplantation and Immunodeficiency. P. Frange receives research support from Sidaction. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 131 - N° 6
P. 1594 - juin 2013 Retour au numéro
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