Abstract
BackgroundTRNT1 (CCA-adding transfer RNA nucleotidyl transferase) enzyme deficiency is a new metabolic disease caused by defective post-transcriptional modification of mitochondrial and cytosolic transfer RNAs (tRNAs).ResultsWe investigated four patients from two families with infantile-onset cyclical, aseptic febrile episodes with vomiting and diarrhoea, global electrolyte imbalance during these episodes, sideroblastic anaemia, B lymphocyte immunodeficiency, retinitis pigmentosa, hepatosplenomegaly, exocrine pancreatic insufficiency and renal tubulopathy. Other clinical features found in children include sensorineural deafness, cerebellar atrophy, brittle hair, partial villous atrophy and nephrocalcinosis.Whole exome sequencing and bioinformatic filtering were utilised to identify recessive compound heterozygous TRNT1 mutations (missense mutation c.668T>C, p.Ile223Thr and a novel splice mutation c.342+5G>T) segregating with disease in the first family. The second family was found to have a homozygous TRNT1 mutation (c.569G>T), p.Arg190Ile, (previously published).We found normal mitochondrial translation products using passage matched controls and functional perturbation of 3’ CCA addition to mitochondrial tRNAs (tRNACys, tRNALeuUUR and tRNAHis) in fibroblasts from two patients, demonstrating a pathomechanism affecting the CCA addition to mt-tRNAs. Acute management of these patients included transfusion for anaemia, fluid and electrolyte replacement and immunoglobulin therapy. We also describe three-year follow-up findings after treatment by bone marrow transplantation in one patient, with resolution of fever and reversal of the abnormal metabolic profile.ConclusionsOur report highlights that TRNT1 mutations cause a spectrum of disease ranging from a childhood-onset complex disease with manifestations in most organs to an adult-onset isolated retinitis pigmentosa presentation. Systematic review of all TRNT1 cases and mutations reported to date revealed a distinctive phenotypic spectrum and metabolic and other investigative findings, which will facilitate rapid clinical recognition of future cases.
Highlights
TRNT1 (CCA-adding transfer RNA nucleotidyl transferase) enzyme deficiency is a new metabolic disease caused by defective post-transcriptional modification of mitochondrial and cytosolic transfer RNAs
In this study we explore a syndrome resulting from the deficiency of TRNT1 (CCA-adding transfer ribonucleic acid (tRNA) nucleotidyl transferase enzyme), which performs an essential posttranscriptional modification by adding on the cytosinecytosine-adenine (CCA) trinucleotide sequence to the 3′ end of all newly produced tRNAs
We explored the functional significance of the TRNT1 mutations in these children and found clear evidence of impaired post-transcriptional modification of mitochondrial transfer ribonucleic acid (mt-tRNA)
Summary
TRNT1 (CCA-adding transfer RNA nucleotidyl transferase) enzyme deficiency is a new metabolic disease caused by defective post-transcriptional modification of mitochondrial and cytosolic transfer RNAs (tRNAs). The CCA trinucleotide sequence is required to accurately attach amino acids, to position the tRNA on the ribosome and to conclude protein translation [9]. In this report we describe four cases including a new family with two severely affected children whose presentation encompassed both sets of clinical features, and in whom we have identified a novel TRNT1 mutation. We explored the functional significance of the TRNT1 mutations in these children and found clear evidence of impaired post-transcriptional modification of mt-tRNAs. We systematically review all the features reported in the cases published far and study the complete clinical phenotype, including a metabolic description that will enable physicians to diagnose this disease clinically and perform targeted genetic investigations
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