Thg1l-flox Mouse

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]. Dysregulations of Thg1l expression are involved in various pathologies like nephropathies and neurodevelopmental disorders [2].

In humans, mutations in Thg1l are associated with autosomal recessive congenital cerebellar ataxia. For example, the homozygous V55A mutation in Thg1l leads to early-onset cerebellar dysfunction, developmental delay, pyramidal signs, and cerebellar atrophy in affected individuals. Fibroblasts from these patients show abnormal mitochondrial networks under obligatory oxidative phosphorylation [1,5]. Compound heterozygous variants in Thg1l also result in autosomal recessive cerebellar ataxia [3]. In the Ashkenazi Jewish population, some compound heterozygous variants expand the phenotypic spectrum of Thg1l-related disorders to include severe epileptic encephalopathy [4].

In conclusion, Thg1l is essential for mitochondrial function and tRNA-histidine modification. Studies on human genetic mutations associated with Thg1l have revealed its role in neurodevelopmental disorders, particularly autosomal recessive congenital cerebellar ataxia and related phenotypes. Understanding Thg1l function through these genetic associations helps in uncovering the molecular mechanisms underlying these diseases, potentially guiding future diagnostic and therapeutic strategies.