TRNT1, encoding tRNA nucleotidyltransferase 1, is an essential enzyme for catalyzing the addition of terminal cytosine-cytosine-adenosine (CCA) trinucleotides to all mature tRNAs, which is crucial for aminoacylation. This process is fundamental for the proper function of tRNAs in translation, a key biological process in cells [4].

Mutations in TRNT1 are associated with diverse phenotypes. Sideroblastic anemia with immunodeficiency, fevers, and developmental delay (SIFD) is an autosomal recessive disorder caused by pathogenic, biallelic variants in TRNT1. Patients may also present with central nervous system, renal, cardiac, ophthalmological features, and sensorineural hearing impairment. GH deficiency, hypoglycemia, and dysmorphic features may be added to the SIFD phenotype [1]. Mutations in TRNT1 are related to heterogeneous phenotypes and multisystem involvement, with immunodeficiency and inflammation as common features. Some patients with early-onset autoinflammatory syndrome due to TRNT1 mutations have been successfully treated with Etanercept [2]. TRNT1 deficiency can lead to a spectrum of diseases, from a childhood-onset complex disease affecting most organs to an adult-onset isolated retinitis pigmentosa [3]. Muscle involvement in the form of mitochondrial myopathy can also occur in TRNT1-related disorders [5]. Mutations may lead to multiple immune abnormalities, especially humoral and cytotoxicity defects [6]. Additionally, hypomorphic variants in TRNT1 can induce a milder autoinflammatory disease with congenital cataracts and impaired sexual development [7].

In conclusion, TRNT1 is essential for tRNA CCA addition, a key step in translation. Studies of TRNT1-associated diseases highlight its role in multiple biological systems, including hematopoiesis, immunity, and development. Understanding the functions of TRNT1 through research on associated diseases helps to reveal the underlying molecular mechanisms of these disorders and may provide insights for potential therapeutic strategies.

References:

1. Odom, John, Amin, Hitha, Gijavanekar, Charul, Potocki, Lorraine, Scaglia, Fernando. 2021. A phenotypic expansion of TRNT1 associated sideroblastic anemia with immunodeficiency, fevers, and developmental delay. In American journal of medical genetics. Part A, 188, 259-268. doi:10.1002/ajmg.a.62482. https://pubmed.ncbi.nlm.nih.gov/34510712/

2. Orlando, Francesca, Naddei, Roberta, Stellacci, Emilia, Tartaglia, Marco, Alessio, Maria. 2021. Etanercept as a successful therapy in autoinflammatory syndrome related to TRNT1 mutations: a case-based review. In Clinical rheumatology, 40, 4341-4348. doi:10.1007/s10067-021-05653-3. https://pubmed.ncbi.nlm.nih.gov/33646446/

3. Wedatilake, Yehani, Niazi, Rojeen, Fassone, Elisa, Clayton, Peter T, Rahman, Shamima. 2016. TRNT1 deficiency: clinical, biochemical and molecular genetic features. In Orphanet journal of rare diseases, 11, 90. doi:10.1186/s13023-016-0477-0. https://pubmed.ncbi.nlm.nih.gov/27370603/

4. Slade, Angelo, Kattini, Ribal, Campbell, Chloe, Holcik, Martin. 2020. Diseases Associated with Defects in tRNA CCA Addition. In International journal of molecular sciences, 21, . doi:10.3390/ijms21113780. https://pubmed.ncbi.nlm.nih.gov/32471101/

5. Wei, Cui-Jie, Liu, Yi-Dan, Yang, Yan-Ling, Liu, Yu-He, Xiong, Hui. 2023. Case report: Muscle involvement in a Chinese patient with TRNT1-related disorder. In Frontiers in pediatrics, 11, 1160107. doi:10.3389/fped.2023.1160107. https://pubmed.ncbi.nlm.nih.gov/37215601/

6. Yang, Lu, Xue, Xiuhong, Zeng, Ting, An, Yunfei, Zhao, Xiaodong. 2020. Novel biallelic TRNT1 mutations lead to atypical SIFD and multiple immune defects. In Genes & diseases, 7, 128-137. doi:10.1016/j.gendis.2020.01.005. https://pubmed.ncbi.nlm.nih.gov/32181284/

7. Bravo García-Morato, María, Padilla-Merlano, Beatriz, Matas Pérez, Elisabet, López-Granados, Eduardo, Rodríguez Pena, Rebeca. . Hypomorphic variant in TRNT1 induces a milder autoinflammatory disease with congenital cataracts and impaired sexual development. In Rheumatology (Oxford, England), 61, e114-e116. doi:10.1093/rheumatology/keab903. https://pubmed.ncbi.nlm.nih.gov/34864912/