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tRNA-HISTIDINE GUANYLYLTRANSFERASE 1-LIKE PROTEIN; THG1L

tRNA-HISTIDINE GUANYLYLTRANSFERASE 1-LIKE PROTEIN; THG1L

Alternative titles; symbolstRNA-HIS GUANYLYLTRANSFERASE 1, S. CEREVISIAE, HOMOLOG OF; THG1INTERPHASE CYTOPLASM FOCI PROTEIN 45; ICF45INDUCED IN HIGH GLUCOSE 1; I...

Alternative titles; symbols

  • tRNA-HIS GUANYLYLTRANSFERASE 1, S. CEREVISIAE, HOMOLOG OF; THG1
  • INTERPHASE CYTOPLASM FOCI PROTEIN 45; ICF45
  • INDUCED IN HIGH GLUCOSE 1; IHG1

HGNC Approved Gene Symbol: THG1L

Cytogenetic location: 5q33.3 Genomic coordinates (GRCh38): 5:157,731,419-157,741,448 (from NCBI)

▼ Description
THG1L is a 3-prime-to-5-prime nucleotidyl transferase that catalyzes the addition of a single guanine to the 5-prime end of tRNA-His (see 590040), an obligatory step in the maturation of tRNA-His. The reaction contains 3 steps, all of which are catalyzed by THG1L: adenylylation, nucleotidyl transfer, and pyrophosphate removal (summary by Hyde et al., 2010).

▼ Cloning and Expression
Guo et al. (2004) cloned human THG1L, which they called ICF45, from a HeLa cell cDNA expression library. The deduced 298-amino acid protein has a predicted molecular mass of 34.8 kD and contains 2 potential N-glycosylation sites, a tyrosine sulfation site, 10 phosphorylation sites, 2 N-myristoylation sites, and an amidation site. Human ICF45 shares 89% amino acid identity with its mouse ortholog, and ICF45 is highly conserved in eukaryotes from yeast to human. RT-PCR analysis detected ICF45 transcripts in all human tissues tested except brain. ICF45 expression was highest in liver and lung, abundant in heart and placenta, weak in skeletal muscle and pancreas, and very low in kidney. Immunofluorescence analysis of HeLa cells showed that endogenous ICF45 was expressed specifically in interphase, located close to the nuclear envelope, and disappeared when cells reached mitosis. In transfected HeLa cells, fluorescence-tagged ICF45 also showed cell cycle-dependent dynamics and a coordinate relation with the centrosome.

Hickey et al. (2011) stated that THG1L, which they called IGH1, contains a putative mitochondrial localization domain. Immunofluorescence analysis showed that epitope-tagged IHG1 localized to mitochondria in transfected HeLa cells and HK2 renal proximal tubule cells. Immunoblot analysis revealed mitochondrial localization for endogenous IGH1 in HeLa and HK2 cells.

▼ Mapping
Gross (2020) mapped the THG1L gene to chromosome 5q33.3 based on an alignment of the THG1L sequence (GenBank BC001852) with the genomic sequence (GRCh38).

▼ Gene Function
Guo et al. (2004) found that knockdown of ICF45 in HeLa cells inhibited cell growth and proliferation, resulting in quiescent cells with polycentrosomes, multiple nuclei, upregulated expression of p53 (TP53; 191170), and increased apoptosis.

Hickey et al. (2011) found that increased Ihg1 expression was associated with increased Pgc1-alpha (PPARGC1A; 604517) protein expression in an in vivo rat model of experimental renal fibrosis. Knockdown or overexpression of IHG1 led to altered mitochondrial biogenesis in HeLa cells, accompanied by differential expression of nuclear genes encoding mitochondrial proteins, including cytochrome c (CYCS; 123970) and MNSOD (SOD2; 147460). IHG1 overexpression increased PGC1-alpha stability, whereas PGC1-alpha overexpression increased IHG1 expression. Furthermore, IHG1 expression correlated with key transcription factors required for mitochondrial biogenesis. Similar results were obtained in HK2 cells. These in vivo and in vitro results suggested that altered levels of PGC1-alpha and its downstream transcription factors alter mitochondrial biogenesis, thereby contributing to pathogenesis of renal fibrosis.

Hickey et al. (2014) showed that knockdown or overexpression of IHG1 altered respiratory capacity, mitochondrial morphology, and mitochondrial fusion in HeLa and HK2 cells. IHG1 localized to mitochondria and formed a complex with the mediators of mitochondrial dynamics MFN1 (608506) and MFN2 (608507). Interaction with IHG1 increased GTP binding to MFN2, thereby enhancing MFN activity and increasing mitochondrial fusion. Furthermore, increased IHG1 expression maintained mitochondria function and cell viability following oxidant stress and protected cells from apoptosis induced by reactive oxygen species.

▼ Biochemical Features
Hyde et al. (2010) determined the crystal structure of human THG1L, which they termed THG1, at 2.3-angstrom resolution. THG1 was a higher-order multimer in solution but crystallized as a highly conserved tetramer. The tetramer appeared to be a dimer of dimers, in which the first dimer constituted the crystal asymmetric unit and the second was generated by symmetry. The THG1 structure closely resembled the structural architecture of canonical 5-prime-to-3-prime DNA polymerases and adenylyl/guanylyl cyclases, both of which use a similar 2-metal-ion mechanism for catalysis.

▼ Molecular Genetics
In 3 sibs of Ashkenazi Jewish descent with autosomal recessive spinocerebellar ataxia-28 (SCAR28; 618800), Edvardson et al. (2016) identified a homozygous missense mutation in the THG1L gene (V55A; 618802.0001). The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family. Analysis of patient fibroblasts showed abnormalities in mitochondrial fusion with increased fragmentation compared to controls when cultured with galactose. The V55A variant showed decreased ability to rescue a growth defect in Thg1-null yeast, although THG1 guanylyltransferase activity was not impaired. Edvardson et al. (2016) hypothesized that the mutation interfered with the ability of THG1L to act as a guanine exchange factor (GEF) for MFN2, thus resulting in disrupted mitochondrial dynamics in Purkinje cells and dendrites in the cerebellum, possibly causing apoptosis.

In 2 unrelated girls, both of Ashkenazi Jewish descent, with SCAR28, Walker et al. (2019) identified a homozygous V55A mutation in the THG1L gene. The mutations, which were found by whole-exome sequencing in 1 patient and by targeted sequencing in the other, segregated with the disorder in both families. Functional studies of the variant and studies of patient cells were not performed. Walker et al. (2019) stated that the variant was found in heterozygous state at a low frequency in the ExAC database, but was not found in the gnomAD database; Hamosh (2020) found the V55A variant in the gnomAD (v2.1.1) database, in heterozygosity only, in 50 of 241,352 alleles, for an allele frequency of 2.07 x 10(-4) (March 11, 2020).

▼ ALLELIC VARIANTS ( 2 Selected Examples):

.0001 SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE 28
THG1L, VAL55ALA
In 3 sibs, born of unrelated parents of Ashkenazi Jewish descent, with autosomal recessive spinocerebellar ataxia-28 (SCAR28; 618800), Edvardson et al. (2016) identified a homozygous c.164T-C transition (c.164T-C, NM_017872) in the THG1L gene, resulting in a val55-to-ala (V55A) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family. The variant was filtered against an in-house database and the ExAC database, where it was not found in the homozygous state. Among 4,975 unrelated Ashkenazi Jewish individuals, 39 were heterozygous carriers for the V55A mutation in the THF1 gene, indicating a carrier rate of 0.8% in this population.

In 2 unrelated girls, both of Ashkenazi Jewish descent, with SCAR28, Walker et al. (2019) identified a homozygous V55A mutation in the THG1L gene. The mutations, which were found by whole-exome sequencing in 1 patient and by targeted sequencing in the other, segregated with the disorder in both families. Functional studies of the variant and studies of patient cells were not performed. Walker et al. (2019) stated that the variant was found in heterozygous state at a low frequency in the ExAC database, but was not found in the gnomAD database; Hamosh (2020) found the V55A variant in the gnomAD (v2.1.1) database, in heterozygosity only, in 50 of 241,352 alleles, for an allele frequency of 2.07 x 10(-4) (March 11, 2020).

.0002 VARIANT OF UNKNOWN SIGNIFICANCE
THG1L, LEU294PRO
This variant is classified as a variant of unknown significance because its contribution to a syndromic form of autosomal recessive spinocerebellar ataxia (see 618800) has not been confirmed.

Shaheen et al. (2019) reported an 18-month-old boy (patient 14DG0824), born of unrelated parents (family 91), with a severe multisystemic growth disorder and cerebellar atrophy, Shaheen et al. (2019) identified a homozygous c.881T-C transition (c.881T-C, NM_017872.3) in the THG1L gene, resulting in a leu294-to-pro (L294P) substitution. The authors also referred to this variant as L249P in supplementary material. The mutation, which was found by exome sequencing, was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed. The patients was ascertained from a cohort of patients from 137 families with congenital microcephaly who underwent exome sequencing.

Tags: 5q33.3