Aberrant tRNA processing causes an autoinflammatory syndrome responsive to TNF inhibitors

Area of Science:

• Genetics and Molecular Biology
• Immunology
• Rare Diseases

Background:

• A recently identified autoinflammatory syndrome is linked to mutations in TRNT1, a gene encoding a tRNA processing enzyme.
• This syndrome, congenital sideroblastic anemia with immunodeficiency, fevers, and developmental delay (SIFD), presents with complex clinical and immune features.

Purpose of the Study:

• To comprehensively characterize the clinical, immunological, and molecular aspects of TRNT1-associated autoinflammatory disease.
• To investigate the therapeutic potential of cytokine inhibitors, specifically TNF inhibitors, in managing the inflammatory phenotype.

Main Methods:

• Studied nine patients with biallelic TRNT1 mutations using whole exome sequencing and candidate gene screening.
• Employed deep RNA and tRNA sequencing, cytokine profiling, immunophenotyping, immunoblotting, and electron microscopy on patient-derived cells.
• Analyzed protein clearance pathways and evaluated treatment responses to TNF inhibitors.

Main Results:

• Identified eight TRNT1 mutations, including three novel ones, in the nine patients.
• Observed elevated serum inflammatory cytokines (IL-6, IFN-γ) and tissue-specific cytokines (TNF, IL-1β) in active disease.
• Detected significant deficiencies in mature cytosolic tRNAs, widespread cellular abnormalities, and dysregulated protein clearance; TNF inhibitor therapy improved inflammation, growth, and reduced transfusion needs.

Conclusions:

• TRNT1 mutations cause a severe, often fatal syndrome connecting protein homeostasis and autoinflammation.
• Early molecular diagnosis is critical for timely initiation of anti-TNF therapy to mitigate severe disease manifestations.