International Journal of Hematology

DOI: 10.1007/s12185-019-02614-0 Pages: 382-389

Atypical SIFD with novel TRNT1 mutations: a case study on the pathogenesis of B-cell deficiency

1. Tokyo Medical and Dental University (TMDU), Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences

2. Tokyo Medical and Dental University (TMDU), Department of Community Pediatrics, Perinatal and Maternal Medicine, Graduate School of Medical and Dental Sciences

3. RIKEN Center for Integrative Medical Sciences, Laboratory for Human Disease Models

4. National Center for Child Health and Development, Center for Postgraduate Education and Training

5. Hiroshima University, Department of Pediatrics, Graduate School of Biomedical and Health Sciences

6. Tokyo Medical and Dental University (TMDU), Department of Child Health and Development, Graduate School of Medical and Dental Sciences

Correspondence to:
Tomohiro Morio
Tel: +81-3-5803-5245



Mutation in the gene encoding tRNA nucleotidyl transferase, CCA-adding 1 (TRNT1), an enzyme essential for the synthesis of the 3′-terminal CCA sequence in tRNA molecules, results in a disorder that features sideroblastic anemia, B-cell immunodeficiency, periodic fever, and developmental delay. Mutations in TRNT1 are also linked to phenotypes including retinitis pigmentosa, cataracts, and cardiomyopathy. To date, it has remained unclear how defective TRNT1 is linked to B-cell deficiency. Here we report the case of a 12-year-old boy without sideroblastic anemia who harbors novel compound heterozygous mutations in TRNT1. Immunophenotypic analysis revealed severely decreased levels of B cells and follicular helper T cells. In the bone marrow, B-cell maturation stopped at the CD19+CD10+CD20+/− pre-B-cell stage. Severe combined immunodeficiency mice transplanted with bone marrow hematopoietic stem cells from the patient showed largely normal B-cell engraftment and differentiation in the bone marrow and periphery at 24 weeks post-transplantation, comparable to those in mouse transplanted with healthy hematopoietic stem cells. Biochemical analysis revealed augmented endoplasmic reticulum (ER) stress response in activated T cells. Peripheral B-cell deficiency of TRNT1 deficiency may be associated with augmented ER stress in immature B cells in the bone marrow.

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