Alternative titles; symbols
HGNC Approved Gene Symbol: TSEN54
SNOMEDCT: 718607001, 718608006;
Cytogenetic location: 17q25.1 Genomic coordinates (GRCh38) : 17:75,516,528-75,524,735 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q25.1 | ?Pontocerebellar hypoplasia type 5 | 610204 | Autosomal recessive | 3 |
| Pontocerebellar hypoplasia type 2A | 277470 | Autosomal recessive | 3 | |
| Pontocerebellar hypoplasia type 4 | 225753 | Autosomal recessive | 3 |
tRNA splicing is a fundamental process required for cell growth and division. SEN54 is a subunit of the tRNA splicing endonuclease, which catalyzes the removal of introns, the first step in tRNA splicing (Paushkin et al., 2004).
By searching sequence databases using yeast Sen54 as probe, Paushkin et al. (2004) identified SEN54. SEN54 contains 526 amino acids and has a calculated molecular mass of 58 kD. Amino acid conservation between human and yeast SEN54 is restricted to the N- and C-terminal regions.
Paushkin et al. (2004) identified and characterized the human tRNA splicing endonuclease. This enzyme consists of SEN2 (608753), SEN34 (608754), SEN15 (608756), and SEN54, homologs of the yeast tRNA endonuclease subunits. Additionally, an alternatively spliced variant of SEN2 is part of a complex with unique RNA endonuclease activity. Paushkin et al. (2004) found that both human endonuclease complexes are associated with CLP1 (608757), a pre-mRNA 3-prime end processing factor. Small interfering RNA-mediated depletion of SEN2 led to defects in maturation of both pre-tRNA and pre-mRNA. These findings demonstrated a link between pre-tRNA splicing and pre-mRNA 3-prime end formation, suggesting that the endonuclease subunits function in multiple RNA processing events.
Budde et al. (2008) showed that TSEN54 is highly expressed in neurons of the pons, cerebellar dentate, and olivary nuclei during the second trimester of pregnancy, a determining period for the morphologic development of these structures. Other brain regions showed low or no staining.
Budde et al. (2008) found the TSEN54 gene in a 3.4-cM interval on chromosome 17q25.1 identified by linkage analysis.
In 42 individuals with pontocerebellar hypoplasia type 2 (PCH2A; 277470), Budde et al. (2008) identified homozygosity for an ala307-to-ser mutation in the TSEN54 gene (A307S; 608755.0001). Budde et al. (2008) also found this mutation in 3 patients with pontocerebellar hypoplasia type 4 (PCH4; 225753); in 1 of these patients, 1 TSEN54 allele carried a ser93-to-pro substitution in addition to the A307S mutation (S93P/A307S; 608755.0002), and in the other 2 patients, compound heterozygosity was found for A307S and a different nonsense mutation.
Cassandrini et al. (2010) identified a homozygous A307S mutation in 7 affected individuals from 6 unrelated Italian families with PCH2A. Two additional patients had a heterozygous A307S mutation: 1 patient with a PCH2A phenotype in whom the second mutation could not be detected, and another patient with a more severe phenotype (PCH4) who was compound heterozygous for A307S and a truncating mutation (608755.0005). Thus, A307S accounted for 16 (89%) of 18 mutant alleles, and haplotype analysis suggested a founder effect.
Namavar et al. (2011) identified homozygosity for the common A307S mutation in the TSEN54 gene in 88 (52.1%) of 169 patients with various forms of pontocerebellar hypoplasia. All homozygous mutation carriers had a phenotype consistent with PCH2A.
Namavar et al. (2011) found that patients homozygous for the common TSEN54 missense mutation A307S had a phenotype consistent with PCH2, whereas those who were compound heterozygous for A307S and a different TSEN54 mutation had a more severe phenotype consistent with PCH4. Functional studies of TSEN54 variants were not performed.
In a patient with pontocerebellar hypoplasia type 5 (PCH5; 610204) reported by Patel et al. (2006), Namavar et al. (2011) identified compound heterozygous mutations in the TSEN54 gene: 1 allele carried the common A307S mutation found in patients with the milder phenotype PCH2A, and the other allele carried a putative splice site mutation (608755.0006). Functional studies of the variants were not performed. Namavar et al. (2011) noted the phenotypic similarity to PCH4, which is caused by compound heterozygosity for A307S and different pathogenic TSEN54 mutations. The findings indicated that biallelic TSEN54 mutations can cause a spectrum of clinical manifestations of PCH.
In 42 individuals with pontocerebellar hypoplasia type 2 (PCH2A; 277470), Budde et al. (2008) identified homozygosity for a 919G-T transversion in the TSEN54 gene, resulting in an ala307-to-ser (A307S) substitution. This mutation is likely due to a single founder event estimated by Budde et al. (2008) to have occurred at least 11 to 16 generations ago. This region of the protein is conserved in mammals and chicken but is not highly conserved in lower organisms. Analysis of 451 Dutch and 279 German control DNA samples yielded no homozygous and only 5 Dutch and 1 German heterozygous genotypes. Additionally, Budde et al. (2008) screened 136 healthy unrelated individuals from Volendam; no homozygous individuals and only 2 heterozygous individuals were identified. Thus, the allele frequency of the 919G-T variant in the PCH2 subjects was 0.884, counting the Volendam subjects as a single data point, and that in the control population was 0.004. These data strongly suggested that the TSEN54 locus is responsible for most cases of PCH2.
Budde et al. (2008) also found the 919G-T mutation in 3 individuals with pontocerebellar hypoplasia type 4 (PCH4; 225753), in isolation on 3 alleles (with compound heterozygosity in 2; see 608755.0003, 608755.0004) and once in a complex mutation with another missense substitution (608755.0002).
Cassandrini et al. (2010) identified a homozygous A307S mutation in 7 affected individuals from 6 unrelated Italian families with PCH2A. Two additional patients had a heterozygous A307S mutation: 1 patient with a PCH2A phenotype in whom the second mutation could not be detected, and another patient with a more severe phenotype (PCH4) who was compound heterozygous for A307S and a truncating mutation (608755.0005). Thus, A307S accounted for 16 (89%) of 18 mutant alleles, and haplotype analysis suggested a founder effect.
In a patient with pontocerebellar hypoplasia type 5 (PCH5; 610204), Namavar et al. (2011) identified compound heterozygosity for the common A307S mutation and a splice site mutation (608755.0006).
In an individual with severe infantile pontocerebellar hypoplasia type 4 (PCH4; 225753), Budde et al. (2008) found on one TSEN54 allele a 227T-C transition in addition to the 919G-T mutation (A307S; 608755.0001), and on the other the 919G-T mutation alone. The 227T-C mutation results in a substitution of proline for serine at codon 93 (S93P). While ser93 is not highly conserved, this residue is situated in an antiparallel beta-sheet, and a proline in that position would likely hamper proper folding.
In a male with infantile lethal pontocerebellar hypoplasia type 4 (PCH4; 225753), previously reported by Barth et al. (2007), Budde et al. (2008) identified compound heterozygosity for the A307S mutation in TSEN54 (608755.0001) and a C-to-T transition at nucleotide 736, resulting in a glutamine-to-stop substitution at codon 246 (Q246X).
In a female with infantile lethal pontocerebellar hypoplasia type 4 (PCH4; 225753), Budde et al. (2008) identified compound heterozygosity for the A307S substitution (608755.0001) in TSEN54 and a C-to-T transition at nucleotide 1027, resulting in a glutamine-to-stop codon substitution at codon 343 (Q343X).
In an Italian infant girl with lethal pontocerebellar hypoplasia type 4 (PCH4; 225753), Cassandrini et al. (2010) identified compound heterozygosity for 2 mutations in the TSEN54 gene: a 14-bp deletion (1170_1183del), resulting in a frameshift and premature termination, and the common A307S mutation (608755.0001). She presented at birth with hypertonia, congenital contractures, and seizures, and died at age 1 month. Brain MRI showed marked cerebellar atrophy with a peculiar cavitation in the hemispheres and vermis, and severe hypoplasia of the brainstem. Neuropathologic examination showed reduced volume of the cerebellar cortex with loss of Purkinje cells and loss of the ventral pontine nuclei. However, there was a regular pattern of the 4-layered cortex. There was a fetal pattern in the inferior olivary nuclei.
In a patient with pontocerebellar hypoplasia type 5 (PCH5; 610204), previously reported by Patel et al. (2006), Namavar et al. (2011) identified compound heterozygous mutations in the TSEN54 gene: a T-to-C transition in intron 5 (c.468+2T-C), predicted to alter a splice site and result in the skipping of exon 5, and the common missense mutation A307S (608755.0001). The splice site variant was not found in 176 control chromosomes. Functional studies of the variants were not performed.
Barth, P. G., Aronica, E., de Vries, L., Nikkels, P. G. J., Scheper, W., Hoozemans, J. J., Poll-The, B.-T., Troost, D. Pontocerebellar hypoplasia type 2: a neuropathological update. Acta Neuropath. 114: 373-386, 2007. [PubMed: 17641900] [Full Text: https://doi.org/10.1007/s00401-007-0263-0]
Budde, B. S., Namavar, Y., Barth, P. G., Poll-The, B. T., Nurnberg, G., Becker, C., van Ruissen, F., Weterman, M. A. J., Fluiter, K., te Beek, E. T., Aronica, E., van der Knaap, M. S., and 26 others. tRNA splicing endonuclease mutations cause pontocerebellar hypoplasia. Nature Genet. 40: 1113-1118, 2008. [PubMed: 18711368] [Full Text: https://doi.org/10.1038/ng.204]
Cassandrini, D., Biancheri, R., Tessa, A., Di Rocco, M., Di Capua, M., Bruno, C., Denora, P. S., Sartori, S., Rossi, A., Nozza, P., Emma, F., Mezzano, P., Politi, M. R., Laverda, A. M., Zara, F., Pavone, L., Simonati, A., Leuzzi, V., Santorelli, F. M., Bertini, E. Pontocerebellar hypoplasia: clinical, pathologic, and genetic studies. Neurology 75: 1459-1464, 2010. [PubMed: 20956791] [Full Text: https://doi.org/10.1212/WNL.0b013e3181f88173]
Namavar, Y., Barth, P. G., Kasher, P. R., van Ruissen, F., Brockmann, K., Bernert, G., Writzl, K., Ventura, K., Cheng, E. Y., Ferriero, D. M., Basel-Vanagaite, L., Eggens, V. R. C., and 12 others. Clinical, neuroradiological and genetic findings in pontocerebellar hypoplasia. Brain 134: 143-156, 2011. [PubMed: 20952379] [Full Text: https://doi.org/10.1093/brain/awq287]
Namavar, Y., Chitayat, D., Barth, P. G., van Ruissen, F., de Wissel, M. B., Poll-The, B. T., Silver, R., Baas, F. TSEN54 mutations cause pontocerebellar hypoplasia type 5. Europ. J. Hum. Genet. 19: 724-726, 2011. [PubMed: 21368912] [Full Text: https://doi.org/10.1038/ejhg.2011.8]
Patel, M. S., Becker, L. E., Toi, A., Armstrong, D. L., Chitayat, D. Severe, fetal-onset form of olivopontocerebellar hypoplasia in three sibs: PCH type 5? Am. J. Med. Genet. 140A: 594-603, 2006. [PubMed: 16470708] [Full Text: https://doi.org/10.1002/ajmg.a.31095]
Paushkin, S. V., Patel, M., Furia, B. S., Peltz, S. W., Trotta, C. R. Identification of a human endonuclease complex reveals a link between tRNA splicing and pre-mRNA 3-prime end formation. Cell 117: 311-321, 2004. [PubMed: 15109492] [Full Text: https://doi.org/10.1016/s0092-8674(04)00342-3]