Abstract
In 2014, a child with broad combined immunodeficiency (CID) who was homozygous for a private BCL10 allele was reported to have complete inherited human BCL10 deficiency. In the present study, we report a new BCL10 mutation in another child with CID who was homozygous for a BCL10 variant (R88X), previously reported as a rare allele in heterozygosis (minor allele frequency, 0.000003986). The mutant allele was a loss-of-expression and loss-of-function allele. As with the previously reported patient, this patient had complete BCL10 deficiency. The clinical phenotype shared features, such as respiratory infections, but differed from that of the previous patient that he did not develop significant gastroenteritis episodes or chronic colitis. Cellular and immunological phenotypes were similar to those of the previous patient. TLR4, TLR2/6, and Dectin-1 responses were found to depend on BCL10 in fibroblasts, and final maturation of T cell and B cell maturation into memory cells was affected. Autosomal-recessive BCL10 deficiency should therefore be considered in children with CID.
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Acknowledgments
We would like to thank the members of the Laboratory of Human Genetics of Infectious Diseases and Sonia García Gómez for their helpful advice. We would also like to thank the patient and his family for participating in this study.
Funding
Support was provided by the Ramon Areces Foundation, through a grant from the XVII Concurso Nacional de Ayudas a la Investigación, FIS grant Ref. PI14/00616, FIS grant Ref. PI17/00543, MINECO grant SAF2014-54708-R and CAM grant B2017/BMD3673. AVDR was provided support by FIS grant Ref. PI17/00543.
The Laboratory of Human Genetics of Infectious Diseases work was funded, in part, by the French National Research Agency (ANR) under the “Investments for the future” program (ANR-10-IAHU-01), Integrative Biology of Emerging Infectious Diseases Laboratoire d’Excellence (ANR-10-LABX-62-IBEID), the Rockefeller University, Institut National de la Santé et de la Recherche Médicale (INSERM), the Howard Hughes Medical Institute, Paris Descartes University, and the St. Giles Foundation.
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Ana Van Den Rym: Sanger sequencing, protein expression, mutagenesis, transfections, and ELISA
Prasad Taur, Ambreen Pandrowala, and Vijaya Gowari: T and B phenotype
Rubén Martinez-Barricarte: CADD versus MAF analysis
Lazaro Lorenzo: Handling of cells, DNA extraction, and PBMC obtention
Anne Puel: Cell handling and manuscript editing
Amin Safa: Sanger sequencing and protein expression
Pablo Gonzalez-Navarro, Victor Toledano, Maria Vela, and Carolina Cubillos-Zapata: Manuscript comments, advice, and editing
Eduardo López-Collazo: Group leader, consulting on experimental procedures
Antonio Pérez-Martínez: Member of the Department of Pediatric Haemato-oncology and Stem Cell Transplantation, consulting for clinical handling and manuscript editing
Silvia Sánchez-Ramón and Maria José Recio: Manuscript comments, advice, and editing
Jean-Laurent Casanova: Manuscript drafting and editing
Mukesh M. Desai: Physician in charge of the patient’s care and head of the laboratory where the T cell and B cell experiments were performed
Rebeca Pérez de Diego: Laboratory head, experiment design, manuscript drafting, and editing. Corresponding author
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Van Den Rym, A., Taur, P., Martinez-Barricarte, R. et al. Human BCL10 Deficiency due to Homozygosity for a Rare Allele. J Clin Immunol 40, 388–398 (2020). https://doi.org/10.1007/s10875-020-00760-3
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DOI: https://doi.org/10.1007/s10875-020-00760-3