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


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.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4


  1. 1.

    Hou YM. CCA addition to tRNA: implications for tRNA quality control. IUBMB Life. 2010;62(4):251–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Wiseman DH, May A, Jolles S, Connor P, Powell C, Heeney MM, et al. A novel syndrome of congenital sideroblastic anemia, B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD). Blood. 2013;122(1):112–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Chakraborty PK, Schmitz-Abe K, Kennedy EK, Mamady H, Naas T, Durie D, et al. Mutations in TRNT1 cause congenital sideroblastic anemia with immunodeficiency, fevers, and developmental delay (SIFD). Blood. 2014;124(18):2867–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Barton C, Kausar S, Kerr D, Bitetti S, Wynn R. SIFD as a novel cause of severe fetal hydrops and neonatal anaemia with iron loading and marked extramedullary haemopoiesis. J Clin Pathol. 2018;71(3):275–8.

    Article  PubMed  Google Scholar 

  5. 5.

    Lougaris V, Chou J, Baronio M, Gazzurelli L, Lorenzini T, Soresina A, et al. Novel biallelic TRNT1 mutations resulting in sideroblastic anemia, combined B and T cell defects, hypogammaglobulinemia, recurrent infections, hypertrophic cardiomyopathy and developmental delay. Clin Immunol. 2018;188:20–2.

    Article  CAS  PubMed  Google Scholar 

  6. 6.

    Wedatilake Y, Niazi R, Fassone E, Powell CA, Pearce S, Plagnol V, et al. TRNT1 deficiency: clinical, biochemical and molecular genetic features. Orphanet J Rare Dis. 2016;11(1):90.

    Article  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Sasarman F, Thiffault I, Weraarpachai W, Salomon S, Maftei C, Gauthier J, et al. The 3′ addition of CCA to mitochondrial tRNASer(AGY) is specifically impaired in patients with mutations in the tRNA nucleotidyl transferase TRNT1. Hum Mol Genet. 2015;24(10):2841–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Frans G, Moens L, Schaballie H, Wuyts G, Liston A, Poesen K, et al. Homozygous N-terminal missense mutation in TRNT1 leads to progressive B-cell immunodeficiency in adulthood. J Allergy Clin Immunol. 2017;139(1):360–.e6.

    Article  CAS  PubMed  Google Scholar 

  9. 9.

    Hull S, Malik AN, Arno G, Mackay DS, Plagnol V, Michaelides M, et al. Expanding the phenotype of TRNT1-related immunodeficiency to include childhood cataract and inner retinal dysfunction. JAMA Ophthalmol. 2016;134(9):1049–53.

    Article  PubMed  Google Scholar 

  10. 10.

    DeLuca AP, Whitmore SS, Barnes J, Sharma TP, Westfall TA, Scott CA, et al. Hypomorphic mutations in TRNT1 cause retinitis pigmentosa with erythrocytic microcytosis. Hum Mol Genet. 2016;25(1):44–56.

    Article  CAS  PubMed  Google Scholar 

  11. 11.

    Leibovitch M, Hanic-Joyce PJ, Joyce PBM. In vitro studies of disease-linked variants of human tRNA nucleotidyltransferase reveal decreased thermal stability and altered catalytic activity. Biochim Biophys Acta Proteins Proteom. 2018;1866(4):527–40.

    Article  CAS  PubMed  Google Scholar 

  12. 12.

    Liwak-Muir U, Mamady H, Naas T, Wylie Q, McBride S, Lines M, et al. Impaired activity of CCA-adding enzyme TRNT1 impacts OXPHOS complexes and cellular respiration in SIFD patient-derived fibroblasts. Orphanet J Rare Dis. 2016;11(1):79.

    Article  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Giannelou A, Wang H, Zhou Q, Park YH, Abu-Asab MS, Ylaya K, et al. Aberrant tRNA processing causes an autoinflammatory syndrome responsive to TNF inhibitors. Ann Rheum Dis. 2018;77(4):612–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Hoshino A, Takashima T, Yoshida K, Morimoto A, Kawahara Y, Yeh TW, et al. Dysregulation of Epstein–Barr virus infection in hypomorphic ZAP70 mutation. J Infect Dis. 2018;218(5):825–34.

    Article  PubMed  CAS  Google Scholar 

  15. 15.

    Takashima T, Okamura M, Yeh TW, Okano T, Yamashita M, Tanaka K, et al. Multicolor flow cytometry for the diagnosis of primary immunodeficiency diseases. J Clin Immunol. 2017;37(5):486–95.

    Article  CAS  PubMed  Google Scholar 

Download references


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 information




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.

Corresponding author

Correspondence to Tomohiro Morio.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

About this article

Verify currency and authenticity via CrossMark

Cite this article

Kumaki, E., Tanaka, K., Imai, K. et al. Atypical SIFD with novel TRNT1 mutations: a case study on the pathogenesis of B-cell deficiency. Int J Hematol 109, 382–389 (2019).

Download citation


  • B-cell deficiency
  • TRNT1
  • SIFD
  • Endoplasmic reticulum stress