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

  • Eri Kumaki
  • Keisuke Tanaka
  • Kohsuke Imai
  • Yuki Aoki-Nogami
  • Akira Ishiguro
  • Satoshi Okada
  • Hirokazu Kanegane
  • Fumihiko Ishikawa
  • Tomohiro MorioEmail author
Original Article


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.


B-cell deficiency TRNT1 SIFD Endoplasmic reticulum stress 



The authors would like to thank Noriko Mitsuiki, Takehiro Takashima, Tzu-Wen Yeh, Tsubasa Okano, and Osamu Ohara for technical assistance. This work was in part supported by grants from Ministry of Health, Labor, and Welfare, JSPS KAKENHI Grant number 26293244 (T. M.)

Author contributions

EK performed the immunological experiments and wrote the manuscript. KT and SO performed the genetic analysis. KI provided critical discussion. YA-N and FI performed the mouse experiments. AI provided clinical information and the samples. HK revised the manuscript. TM designed the study and revised the manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

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Copyright information

© Japanese Society of Hematology 2019

Authors and Affiliations

  1. 1.Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental SciencesTokyo Medical and Dental University (TMDU)TokyoJapan
  2. 2.Department of Community Pediatrics, Perinatal and Maternal Medicine, Graduate School of Medical and Dental SciencesTokyo Medical and Dental University (TMDU)TokyoJapan
  3. 3.Laboratory for Human Disease ModelsRIKEN Center for Integrative Medical SciencesYokohamaJapan
  4. 4.Center for Postgraduate Education and TrainingNational Center for Child Health and DevelopmentTokyoJapan
  5. 5.Department of Pediatrics, Graduate School of Biomedical and Health SciencesHiroshima UniversityHiroshimaJapan
  6. 6.Department of Child Health and Development, Graduate School of Medical and Dental SciencesTokyo Medical and Dental University (TMDU)TokyoJapan

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