Whole-exome sequencing identifies Coronin-1A deficiency in 3 siblings with immunodeficiency and EBV-associated B-cell lymphoproliferation

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• 作者：Despina Moshous ; MD ; PhD^a ; ^b ; ^c ; ^&lowast ; ; ^{despina.moshous@inserm.fr} ; Emmanuel Martin ; PhD^a ; ^b ; ^&lowast ; ; 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 ; Sté ; phane Blanche ; MD^b ; ^c ; Patrick Revy ; PhD^a ; ^b ; Alain Fischer ; MD ; PhD^a ; ^b ; ^c ; Sylvain Latour ; PhD^a ; ^b ; ^&lowast ; ; Nada Jabado ; MD ; PhD^h ; ⁱ ; ⁿ ; ^&lowast ; ; Jean-Pierre de Villartay ; PhD^a ; ^b ; ^c
• 关键词：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
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2013
• 出版时间：June, 2013
• 年：2013
• 卷：131
• 期：6
• 页码：1594-1603.e9
• 全文大小：2815 K

文摘

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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, 7?, 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 ¦Â-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.