Thg1l, also known as induced in high glucose-1 (IHG-1), encodes an essential mitochondria-associated protein. It catalyzes the 3'-5' addition of guanine to the 5'-end of tRNA-histidine (tRNAHis), playing crucial roles in mitochondrial biogenesis, dynamics, ATP production, apoptosis modulation, cell-cycle progression, survival, cellular stress responses, and redox homeostasis [2].

Mutations in Thg1l are associated with various neurodevelopmental disorders. For instance, the homozygous V55A mutation in Thg1l has been found in patients with early onset cerebellar dysfunction, developmental delay, pyramidal signs, and cerebellar atrophy. Fibroblasts from these patients show abnormal mitochondrial networks under oxidative phosphorylation conditions [1,5]. Compound heterozygous variants in Thg1l can also lead to autosomal recessive cerebellar ataxia, expanding the gene variation and clinical spectrum [3]. In the Ashkenazi Jewish population, biallelic variants in Thg1l result in phenotypes ranging from severe epileptic encephalopathy (in compound heterozygotes) to milder cerebellar ataxia with normal/near-normal cognition (in homozygotes for p.(Val55Ala)) [4].

In conclusion, Thg1l is essential for mitochondrial function and tRNA-histidine modification. Research on Thg1l-related mutations in patients has revealed its significance in neurodevelopmental disorders, especially cerebellar ataxia and associated neurological phenotypes. Understanding Thg1l's function provides insights into the mechanisms underlying these disorders, potentially guiding future diagnostic and therapeutic strategies.

References:

1. Walker, Melissa A, Lerman-Sagie, Tally, Swoboda, Kathryn, Lev, Dorit, Blumkin, Lubov. 2019. Refining the phenotype of the THG1L (p.Val55Ala mutation)-related mitochondrial autosomal recessive congenital cerebellar ataxia. In American journal of medical genetics. Part A, 179, 1575-1579. doi:10.1002/ajmg.a.61196. https://pubmed.ncbi.nlm.nih.gov/31168944/

2. Martini, Davide, De Cesari, Chiara, Digregorio, Matteo, Giannaccini, Martina, Andreazzoli, Massimiliano. 2024. Expression analysis of thg1l during Xenopus laevis development. In The International journal of developmental biology, 68, 85-91. doi:10.1387/ijdb.240033ma. https://pubmed.ncbi.nlm.nih.gov/39016375/

3. Han, Rui, Chu, Manman, Gao, Jinshuang, Jia, Tianming, Zhang, Xiaoli. 2023. Compound heterozygous variants of THG1L result in autosomal recessive cerebellar ataxia. In Journal of human genetics, 68, 843-848. doi:10.1038/s10038-023-01192-8. https://pubmed.ncbi.nlm.nih.gov/37670026/

4. Rabin, Rachel, Hirsch, Yoel, Johansson, Martin M, Ekstein, Ahron, Pappas, John. 2021. Severe epileptic encephalopathy associated with compound heterozygosity of THG1L variants in the Ashkenazi Jewish population. In American journal of medical genetics. Part A, 185, 1589-1597. doi:10.1002/ajmg.a.62147. https://pubmed.ncbi.nlm.nih.gov/33682303/

5. Edvardson, Simon, Elbaz-Alon, Yael, Jalas, Chaim, Jackman, Jane E, Elpeleg, Orly. 2016. A mutation in the THG1L gene in a family with cerebellar ataxia and developmental delay. In Neurogenetics, 17, 219-225. doi:. https://pubmed.ncbi.nlm.nih.gov/27307223/