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*617057
Table of Contents
Alternative titles; symbols
HGNC Approved Gene Symbol: CTU2
Cytogenetic location: 16q24.3 Genomic coordinates (GRCh38) : 16:88,706,503-88,715,396 (from NCBI)
Modified nucleosides close to the anticodon in tRNAs are important for proper decoding of mRNA by the ribosome. Particularly, thiolation of the wobble uridine at position 34 (U34) of tRNA-lys(UUU) (see 189918), tRNA-glu(UUC) (see 180640), and tRNA-gly(UUG) (see 189911) occurs in nearly all species. CTU2 is a subunit of a highly conserved protein complex involved in thiolation of wobble U34 (Dewez et al., 2008).
By database analysis, Dewez et al. (2008) identified human CTU2 based on its homology with its fission yeast ortholog. The deduced protein contains an approximately 350-amino acid region that shares a high degree of conservation with lower eukaryotes.
By mass spectrometric analysis of proteins that interacted with epitope-tagged ATPBD3 (CTU1; 612694) in HEK293T cells, Schlieker et al. (2008) identified CTU2, which they called UPF0432. The deduced protein shares similarity with PP-loop ATP pyrophosphatases, suggesting that it is a tRNA-modifying enzyme.
Hartz (2016) mapped the CTU2 gene to chromosome 16q24.3 based on an alignment of the CTU2 sequence (GenBank BC021056) with the genomic sequence (GRCh38).
By immunoprecipitation and mass spectrometric analyses, Schlieker et al. (2008) found that URM1 (612693) and UPF0432 interacted with epitope-tagged ATPBD3 in transfected HEK293T cells. UPF0432 appeared to associate directly with ATPBD3, but not with URM1. Knockdown of URM1 or ATPBD3 in HeLa cells reduced thiolation of uracil in the anticodon region of tRNA-lys(UUU), suggesting that the complex represents the human ortholog of yeast cytosolic thiouridylase.
Rapino et al. (2018) showed in humans that the enzymes that catalyze modifications of wobble uridine-34 (U34) tRNA are key players of the protein synthesis rewiring that is induced by the transformation driven by the BRAF V600E (164757.0001) oncogene and by resistance to targeted therapy in melanoma. Rapino et al. (2018) showed that BRAF V600E-expressing melanoma cells are dependent on U34 enzymes for survival, and that concurrent inhibition of MAPK signaling and ELP3 (612722) or CTU1 and/or CTU2 synergizes to kill melanoma cells. Activation of the PI3K signaling pathway, one of the most common mechanisms of acquired resistance to MAPK therapeutic agents, markedly increases the expression of U34 enzymes. Mechanistically, U34 enzymes promote glycolysis in melanoma cells through the direct, codon-dependent, regulation of the translation of HIF1A (603348) mRNA and the maintenance of high levels of HIF1-alpha protein. Therefore, the acquired resistance to anti-BRAF therapy is associated with high levels of U34 enzymes and HIF1-alpha. Rapino et al. (2018) concluded that U34 enzymes promote the survival and resistance to therapy of melanoma cells by regulating specific mRNA translation.
Microcephaly, Facial Dysmorphism, Renal Agenesis, and Ambiguous Genitalia Syndrome
In 3 boys from 3 consanguineous Saudi families with microcephaly, facial dysmorphism, renal agenesis, and ambiguous genitalia syndrome (MFRG; 618142), Shaheen et al. (2016) identified homozygosity for a synonymous mutation in the CTU2 gene (T247T; 617057.0001) that was shown to impair splicing and result in a premature termination codon.
In 2 male cousins from the United Arab Emirates with MFRG, Shaheen et al. (2016) identified homozygosity for the previously detected T247T mutation in the CTU2 gene.
In 10 patients from 9 families with MFRG, Shaheen et al. (2019) reported homozygosity for mutations in the CTU2 gene. Five patients had been previously reported (Shaheen et al. (2016, 2016)), all of whom had the founder mutation (617057.0001). The 5 patients not previously reported included 1 with a homozygous truncating mutation (617057.0002), 2 from different families with the same missense mutation (L63P; 617057.0003), 1 with a rare noncanonic splice mutation (617057.0004), and 1 with a 4-bp deletion (617057.0005). Functional studies showed that these variants significantly impaired wobble uridine thiolation in all known thiol-containing tRNAs.
Among 119 fetuses with structural anomalies from a highly consanguineous population in Saudi Arabia, Al-Hamed et al. (2022) identified 3 fetuses who had the founder T247T mutation in the CTU2 gene by exome sequencing. The fetuses, all conceived by consanguineous parents, had multisystem disease consistent with the findings of MFRG.
In 3 boys from 3 consanguineous Saudi families with microcephaly, facial dysmorphism, renal agenesis, and ambiguous genitalia syndrome (MFRG; 618142), Shaheen et al. (2016) identified homozygosity for a c.873G-A transition (c.873G-A, NM_001012762.1) in the CTU2 gene, resulting in a synonymous thr247-to-thr (T247T) substitution. RT-PCR demonstrated that the mutation impairs normal splicing, causing a frameshift resulting in a premature termination codon (Thr247AlafsTer21).
In 2 male cousins from a consanguineous family from the United Arab Emirates with MFRG, Shaheen et al. (2016) identified homozygosity for the T247T variant on the same haplotype background. The authors stated that the carrier frequency of this founder mutation was 1 in 769 individuals in Saudi Arabia, and noted that the apparently synonymous nature of the causal variant might play a role in underdiagnosis of this syndrome.
Using exome sequencing in 119 fetuses with structural anomalies from a highly consanguineous population in Saudi Arabia, Al-Hamed et al. (2022) identified the T247T founder variant in 3 fetuses with features consistent with MFRG.
In a 2-year-old boy (family 5) with microcephaly, facial dysmorphism, renal agenesis, and ambiguous genitalia syndrome (MFRG; 618142), Shaheen et al. (2019) reported homozygosity for a 1-basepair duplication (c.1206dupT, NM_001012759) in the CTU2 gene, resulting in a frameshift and predicted premature truncation (Ala403Cysfs*23). Functional studies in patient cells showed that the mutation impaired wobble uridine thiolation in all known thiol-containing tRNAs. The mutation was absent from the gomAD database.
In 2 patients (family 6 and 7) with microcephaly, facial dysmorphism, renal agenesis, and ambiguous genitalia syndrome (MFRG; 618142) from 2 unrelated families, Shaheen et al. (2019) reported homozygosity for a c.188T-C transition (c.188T-C, NM_001012759) in the CTU2 gene, resulting in a leu63-to-pro (L63P) substitution in a highly conserved residue. Functional studies in patient cells showed that the mutation impaired wobble uridine thiolation in all known thiol-containing tRNAs. The mutation was found at a low frequency in the gnomAD database (7.6 x 10(-4)).
In a 7-month-old girl (family 8) with microcephaly, facial dysmorphism, renal agenesis, and ambiguous genitalia syndrome (MFRG; 618142), Shaheen et al. (2019) identified homozygosity for a c.282+5G-A transition (c.282+5G-A, NM_001012759) downstream of exon 4 in the CTU2 gene, confirmed by RT-PCR to result in abnormal splicing leading to complete skipping of exons 3 and 4 (Asp49AlafsTer2). Functional studies in patient cells showed that the mutation impaired wobble uridine thiolation in all known thiol-containing tRNAs. The mutation was found at a low frequency in the gnomAD database (4.0 x 10(-6)).
In a 19-year-old woman (family 9) with microcephaly, facial dysmorphism, renal agenesis, and ambiguous genitalia syndrome (MFRG; 618142), Shaheen et al. (2019) identified homozygosity for a 4-bp deletion (c.1514_1517delTTGA, NM_001012759) in the CTU2 gene, resulting in a frameshift and predicted premature protein truncation (Ile505ArgfsTer41). Functional studies in patient cells showed that the mutation impaired wobble uridine thiolation in all known thiol-containing tRNAs. The mutation was found at a low frequency in the gnomAD database (8.0 x 10(-6)).
Al-Hamed, M. H., Kurdi, W., Khan, R., Tulbah, M., AlNemer, M., AlSahan, N., AlMugbel, M., Rafiullah, R., Assoum, M., Monies, D., Shah, Z., Rahbeeni, Z., and 23 others. Prenatal exome sequencing and chromosomal microarray analysis in fetal structural anomalies in a highly consanguineous population reveals a propensity of ciliopathy genes causing multisystem phenotypes. Hum. Genet. 141: 101-126, 2022. [PubMed: 34853893, related citations] [Full Text]
Dewez, M., Bauer, F., Dieu, M., Raes, M., Vandenhaute, J., Hermand, D. The conserved wobble uridine tRNA thiolase Ctu1-Ctu2 is required to maintain genome integrity. Proc. Nat. Acad. Sci. 105: 5459-5464, 2008. [PubMed: 18391219, related citations] [Full Text]
Hartz, P. A. Personal Communication. Baltimore, Md. 7/27/2016.
Rapino, F., Delaunay, S., Rambow, F., Zhou, Z., Tharun, L., De Tullio, P., Sin, O., Shostak, K., Schmitz, S., Piepers, J., Ghesquiere, B., Karim, L., and 17 others. Codon-specific translation reprogramming promotes resistance to targeted therapy. Nature 558: 605-609, 2018. Note: Erratum: Nature 599: E14, 2021. [PubMed: 29925953, related citations] [Full Text]
Schlieker, C. D., Van der Veen, A. G., Damon, J. R., Spooner, E., Ploegh, H. L. A functional proteomics approach links the ubiquitin-related modifier Urm1 to a tRNA modification pathway. Proc. Nat. Acad. Sci. 105: 18255-18260, 2008. [PubMed: 19017811, related citations] [Full Text]
Shaheen, R., Al-Salam, Z., El-Hattab, A. W., Alkuraya, F. S. The syndrome of dysmorphic facies, renal agenesis, ambiguous genitalia, microcephaly, polydactyly and lissencephaly (DREAM-PL): report of two additional patients. Am. J. Med. Genet. 170A: 3222-3226, 2016. [PubMed: 27480277, related citations] [Full Text]
Shaheen, R., Mark, P., Prevost, C. T., AlKindi, A., Alhag, A., Estwani, F., Al-Sheddi, T., Alobeid, E., Alenazi, M. M., Ewida, N., Ibrahim, N., Hashem, M., and 12 others. Biallelic variants in CTU2 cause DREAM-PL syndrome and impair thiolation of tRNA wobble U34. Hum. Mutat. 40: 2108-2120, 2019. Note: Erratum: Hum. Mutat. 42: 219 only, 2021. [PubMed: 31301155, related citations] [Full Text]
Shaheen, R., Patel, N., Shamseldin, H., Alzahrani, F., Al-Yamany, R., ALMoisheer, A., Ewida, N., Anazi, S., Alnemer, M., Elsheikh, M., Alfaleh, K., Alshammari, M., and 13 others. Accelerating matchmaking of novel dysmorphology syndromes through clinical and genomic characterization of a large cohort. Genet. Med. 18: 686-695, 2016. [PubMed: 26633546, related citations] [Full Text]
Alternative titles; symbols
HGNC Approved Gene Symbol: CTU2
Cytogenetic location: 16q24.3 Genomic coordinates (GRCh38) : 16:88,706,503-88,715,396 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16q24.3 | Microcephaly, facial dysmorphism, renal agenesis, and ambiguous genitalia syndrome | 618142 | Autosomal recessive | 3 |
Modified nucleosides close to the anticodon in tRNAs are important for proper decoding of mRNA by the ribosome. Particularly, thiolation of the wobble uridine at position 34 (U34) of tRNA-lys(UUU) (see 189918), tRNA-glu(UUC) (see 180640), and tRNA-gly(UUG) (see 189911) occurs in nearly all species. CTU2 is a subunit of a highly conserved protein complex involved in thiolation of wobble U34 (Dewez et al., 2008).
By database analysis, Dewez et al. (2008) identified human CTU2 based on its homology with its fission yeast ortholog. The deduced protein contains an approximately 350-amino acid region that shares a high degree of conservation with lower eukaryotes.
By mass spectrometric analysis of proteins that interacted with epitope-tagged ATPBD3 (CTU1; 612694) in HEK293T cells, Schlieker et al. (2008) identified CTU2, which they called UPF0432. The deduced protein shares similarity with PP-loop ATP pyrophosphatases, suggesting that it is a tRNA-modifying enzyme.
Hartz (2016) mapped the CTU2 gene to chromosome 16q24.3 based on an alignment of the CTU2 sequence (GenBank BC021056) with the genomic sequence (GRCh38).
By immunoprecipitation and mass spectrometric analyses, Schlieker et al. (2008) found that URM1 (612693) and UPF0432 interacted with epitope-tagged ATPBD3 in transfected HEK293T cells. UPF0432 appeared to associate directly with ATPBD3, but not with URM1. Knockdown of URM1 or ATPBD3 in HeLa cells reduced thiolation of uracil in the anticodon region of tRNA-lys(UUU), suggesting that the complex represents the human ortholog of yeast cytosolic thiouridylase.
Rapino et al. (2018) showed in humans that the enzymes that catalyze modifications of wobble uridine-34 (U34) tRNA are key players of the protein synthesis rewiring that is induced by the transformation driven by the BRAF V600E (164757.0001) oncogene and by resistance to targeted therapy in melanoma. Rapino et al. (2018) showed that BRAF V600E-expressing melanoma cells are dependent on U34 enzymes for survival, and that concurrent inhibition of MAPK signaling and ELP3 (612722) or CTU1 and/or CTU2 synergizes to kill melanoma cells. Activation of the PI3K signaling pathway, one of the most common mechanisms of acquired resistance to MAPK therapeutic agents, markedly increases the expression of U34 enzymes. Mechanistically, U34 enzymes promote glycolysis in melanoma cells through the direct, codon-dependent, regulation of the translation of HIF1A (603348) mRNA and the maintenance of high levels of HIF1-alpha protein. Therefore, the acquired resistance to anti-BRAF therapy is associated with high levels of U34 enzymes and HIF1-alpha. Rapino et al. (2018) concluded that U34 enzymes promote the survival and resistance to therapy of melanoma cells by regulating specific mRNA translation.
Microcephaly, Facial Dysmorphism, Renal Agenesis, and Ambiguous Genitalia Syndrome
In 3 boys from 3 consanguineous Saudi families with microcephaly, facial dysmorphism, renal agenesis, and ambiguous genitalia syndrome (MFRG; 618142), Shaheen et al. (2016) identified homozygosity for a synonymous mutation in the CTU2 gene (T247T; 617057.0001) that was shown to impair splicing and result in a premature termination codon.
In 2 male cousins from the United Arab Emirates with MFRG, Shaheen et al. (2016) identified homozygosity for the previously detected T247T mutation in the CTU2 gene.
In 10 patients from 9 families with MFRG, Shaheen et al. (2019) reported homozygosity for mutations in the CTU2 gene. Five patients had been previously reported (Shaheen et al. (2016, 2016)), all of whom had the founder mutation (617057.0001). The 5 patients not previously reported included 1 with a homozygous truncating mutation (617057.0002), 2 from different families with the same missense mutation (L63P; 617057.0003), 1 with a rare noncanonic splice mutation (617057.0004), and 1 with a 4-bp deletion (617057.0005). Functional studies showed that these variants significantly impaired wobble uridine thiolation in all known thiol-containing tRNAs.
Among 119 fetuses with structural anomalies from a highly consanguineous population in Saudi Arabia, Al-Hamed et al. (2022) identified 3 fetuses who had the founder T247T mutation in the CTU2 gene by exome sequencing. The fetuses, all conceived by consanguineous parents, had multisystem disease consistent with the findings of MFRG.
In 3 boys from 3 consanguineous Saudi families with microcephaly, facial dysmorphism, renal agenesis, and ambiguous genitalia syndrome (MFRG; 618142), Shaheen et al. (2016) identified homozygosity for a c.873G-A transition (c.873G-A, NM_001012762.1) in the CTU2 gene, resulting in a synonymous thr247-to-thr (T247T) substitution. RT-PCR demonstrated that the mutation impairs normal splicing, causing a frameshift resulting in a premature termination codon (Thr247AlafsTer21).
In 2 male cousins from a consanguineous family from the United Arab Emirates with MFRG, Shaheen et al. (2016) identified homozygosity for the T247T variant on the same haplotype background. The authors stated that the carrier frequency of this founder mutation was 1 in 769 individuals in Saudi Arabia, and noted that the apparently synonymous nature of the causal variant might play a role in underdiagnosis of this syndrome.
Using exome sequencing in 119 fetuses with structural anomalies from a highly consanguineous population in Saudi Arabia, Al-Hamed et al. (2022) identified the T247T founder variant in 3 fetuses with features consistent with MFRG.
In a 2-year-old boy (family 5) with microcephaly, facial dysmorphism, renal agenesis, and ambiguous genitalia syndrome (MFRG; 618142), Shaheen et al. (2019) reported homozygosity for a 1-basepair duplication (c.1206dupT, NM_001012759) in the CTU2 gene, resulting in a frameshift and predicted premature truncation (Ala403Cysfs*23). Functional studies in patient cells showed that the mutation impaired wobble uridine thiolation in all known thiol-containing tRNAs. The mutation was absent from the gomAD database.
In 2 patients (family 6 and 7) with microcephaly, facial dysmorphism, renal agenesis, and ambiguous genitalia syndrome (MFRG; 618142) from 2 unrelated families, Shaheen et al. (2019) reported homozygosity for a c.188T-C transition (c.188T-C, NM_001012759) in the CTU2 gene, resulting in a leu63-to-pro (L63P) substitution in a highly conserved residue. Functional studies in patient cells showed that the mutation impaired wobble uridine thiolation in all known thiol-containing tRNAs. The mutation was found at a low frequency in the gnomAD database (7.6 x 10(-4)).
In a 7-month-old girl (family 8) with microcephaly, facial dysmorphism, renal agenesis, and ambiguous genitalia syndrome (MFRG; 618142), Shaheen et al. (2019) identified homozygosity for a c.282+5G-A transition (c.282+5G-A, NM_001012759) downstream of exon 4 in the CTU2 gene, confirmed by RT-PCR to result in abnormal splicing leading to complete skipping of exons 3 and 4 (Asp49AlafsTer2). Functional studies in patient cells showed that the mutation impaired wobble uridine thiolation in all known thiol-containing tRNAs. The mutation was found at a low frequency in the gnomAD database (4.0 x 10(-6)).
In a 19-year-old woman (family 9) with microcephaly, facial dysmorphism, renal agenesis, and ambiguous genitalia syndrome (MFRG; 618142), Shaheen et al. (2019) identified homozygosity for a 4-bp deletion (c.1514_1517delTTGA, NM_001012759) in the CTU2 gene, resulting in a frameshift and predicted premature protein truncation (Ile505ArgfsTer41). Functional studies in patient cells showed that the mutation impaired wobble uridine thiolation in all known thiol-containing tRNAs. The mutation was found at a low frequency in the gnomAD database (8.0 x 10(-6)).
Al-Hamed, M. H., Kurdi, W., Khan, R., Tulbah, M., AlNemer, M., AlSahan, N., AlMugbel, M., Rafiullah, R., Assoum, M., Monies, D., Shah, Z., Rahbeeni, Z., and 23 others. Prenatal exome sequencing and chromosomal microarray analysis in fetal structural anomalies in a highly consanguineous population reveals a propensity of ciliopathy genes causing multisystem phenotypes. Hum. Genet. 141: 101-126, 2022. [PubMed: 34853893] [Full Text: https://doi.org/10.1007/s00439-021-02406-9]
Dewez, M., Bauer, F., Dieu, M., Raes, M., Vandenhaute, J., Hermand, D. The conserved wobble uridine tRNA thiolase Ctu1-Ctu2 is required to maintain genome integrity. Proc. Nat. Acad. Sci. 105: 5459-5464, 2008. [PubMed: 18391219] [Full Text: https://doi.org/10.1073/pnas.0709404105]
Hartz, P. A. Personal Communication. Baltimore, Md. 7/27/2016.
Rapino, F., Delaunay, S., Rambow, F., Zhou, Z., Tharun, L., De Tullio, P., Sin, O., Shostak, K., Schmitz, S., Piepers, J., Ghesquiere, B., Karim, L., and 17 others. Codon-specific translation reprogramming promotes resistance to targeted therapy. Nature 558: 605-609, 2018. Note: Erratum: Nature 599: E14, 2021. [PubMed: 29925953] [Full Text: https://doi.org/10.1038/s41586-018-0243-7]
Schlieker, C. D., Van der Veen, A. G., Damon, J. R., Spooner, E., Ploegh, H. L. A functional proteomics approach links the ubiquitin-related modifier Urm1 to a tRNA modification pathway. Proc. Nat. Acad. Sci. 105: 18255-18260, 2008. [PubMed: 19017811] [Full Text: https://doi.org/10.1073/pnas.0808756105]
Shaheen, R., Al-Salam, Z., El-Hattab, A. W., Alkuraya, F. S. The syndrome of dysmorphic facies, renal agenesis, ambiguous genitalia, microcephaly, polydactyly and lissencephaly (DREAM-PL): report of two additional patients. Am. J. Med. Genet. 170A: 3222-3226, 2016. [PubMed: 27480277] [Full Text: https://doi.org/10.1002/ajmg.a.37877]
Shaheen, R., Mark, P., Prevost, C. T., AlKindi, A., Alhag, A., Estwani, F., Al-Sheddi, T., Alobeid, E., Alenazi, M. M., Ewida, N., Ibrahim, N., Hashem, M., and 12 others. Biallelic variants in CTU2 cause DREAM-PL syndrome and impair thiolation of tRNA wobble U34. Hum. Mutat. 40: 2108-2120, 2019. Note: Erratum: Hum. Mutat. 42: 219 only, 2021. [PubMed: 31301155] [Full Text: https://doi.org/10.1002/humu.23870]
Shaheen, R., Patel, N., Shamseldin, H., Alzahrani, F., Al-Yamany, R., ALMoisheer, A., Ewida, N., Anazi, S., Alnemer, M., Elsheikh, M., Alfaleh, K., Alshammari, M., and 13 others. Accelerating matchmaking of novel dysmorphology syndromes through clinical and genomic characterization of a large cohort. Genet. Med. 18: 686-695, 2016. [PubMed: 26633546] [Full Text: https://doi.org/10.1038/gim.2015.147]
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