TRNT1 missense mutations define an autoinflammatory disease characterized by recurrent fever, severe anemia, and B-cell immunodeficiency. M. Stoffels1, Q. Zhou1, A. Giannelou2, D. Stone1, A. Sediva3, S. Rosenzweig4, J. Edwan2, M. Pelletier2, K. Bishop5, B. Carrington5, R. Sood5, E. F. Remmers1, K. Barron6, I. Aksentijevich1, D. L. Kastner1 1) Inflammatory Disease Section, NHGRI, Bethesda, MD., USA; 2) National Institute for Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD, USA; 3) University Hospital Motol, Prague, Czech Republic; 4) National Institutes of Health, Bethesda, MD, USA; 5) Zebrafish Core, NHGRI, Bethesda, MD, USA; 6) National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA.

   We observed a syndrome characterized by recurrent fever, severe anemia, gastrointestinal symptoms, and a spectrum of immunologic and neurologic symptoms in five children from four unrelated families. Neurologic manifestations ranged from mild developmental delay to nystagmus, spasticity, optic nerve atrophy, and sensorineural hearing loss. Sideroblastic anemia was identified by bone marrow biopsies in two of the children. We performed whole-exome sequencing in three unrelated families. After filtering for novel and rare variants (allele frequency <1:1000) and homozygous recessive inheritance in the first two families, we observed that the patients carried missense mutations in TRNT1, encoding tRNA nucleotidyl transferase, CCA-adding, 1. By additional exome and Sanger sequencing we found two other patients with mutations in TRNT1. The TRNT1 enzyme catalyzes the addition of the CCA terminus to the 3-prime end of tRNA precursors. All disease associated mutations affect highly conserved amino acid residues and are predicted to be damaging to the protein function. The first consanguineous family from Saudi Arabia had two affected daughters, both homozygous for the p.H215R mutation; the second family of mixed Czech and British background had one affected son, carrying a compound heterozygous p.I223T/p.D163V mutation; two families of mixed European ancestry from the US each had one affected daughter, both compound heterozygous for a p.R99W/p.D163V mutation. Two out of five patients died. The p.H215R mutation was not found in any public database or in 1061 Arabian control DNA samples. The three Caucasian mutations are either novel, or found at a very low allele frequency, consistent with recessive inheritance. Cytokine profiling revealed increased IL-6 serum levels in two out of three tested patients. We observed impaired maturation of CD10-CD20+ B cells in bone marrow aspirates. Knockdown of the zebrafish TRNT1 homologue caused hydrocephaly, defects in tail development, anemia, and a reduction in the number of hair cells present in the lateral line, which subserves functions of the inner ear in zebrafish. In conclusion, our data demonstrate that missense mutations in TRNT1 are associated with an autoinflammatory disease manifesting with fevers, transfusion dependent anemia, gastrointestinal symptoms, immunologic, and neurologic features.

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