Alternative titles; symbols
HGNC Approved Gene Symbol: THOC6
SNOMEDCT: 773554009;
Cytogenetic location: 16p13.3 Genomic coordinates (GRCh38) : 16:3,024,035-3,027,750 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16p13.3 | Beaulieu-Boycott-Innes syndrome | 613680 | Autosomal recessive | 3 |
The THOC6 gene encodes a subunit of the THO complex, which is involved in coordinating mRNA processing with export. The THO complex is a component of the TREX (transcription/export) complex (summary by Beaulieu et al., 2013).
By mass spectrometric analysis of proteins that coimmunoprecipitated with UAP56 (DDX39B; 142560) from HeLa cell nuclear extracts, followed by PCR, Masuda et al. (2005) cloned THOC6, which they designated FSAP35. The deduced protein contains a WD40 repeat domain. THOC6 had an apparent molecular mass of 35 kD by SDS-PAGE.
Using immunoprecipitation and mass spectrometric analysis of HeLa cell nuclear extracts, Masuda et al. (2005) found that the human TREX complex contained THO2 (THOC2; 300395), FSAP79 (THOC5; 612733), HPR1 (THOC1; 606930), UAP56, TEX1 (THOC3; 606929), FSAP35, ALY (THOC4; 604171), and FSAP24 (THOC7; 611965). Immunodepletion and gel-filtration analyses revealed that THO2, HPR1, FSAP79, FSAP35, and FSAP24 were tightly associated in the THO complex, whereas UAP56, ALY, and TEX1 were more loosely associated. Immunoprecipitation of any TREX component efficiently immunoprecipitated spliced mRNA and cDNA transcripts, but not unspliced pre-mRNAs. Immunodepletion of any component had no effect on spliceosome assembly, splicing, or RNA stability. The TREX complex assembled on every mRNA examined. Mutation analysis showed that the C terminus of ALY was required for binding of both UAP56 and the THO complex. The C terminus of UAP56 was sufficient for ALY binding. The N terminus of UAP56 interacted weakly with the THO complex and TEX1, suggesting that other regions of UAP56 are required for maximal binding. Masuda et al. (2005) concluded that recruitment of the human TREX complex is not directly coupled to transcription, as in yeast.
Hartz (2013) mapped the THOC6 gene to chromosome 16p13.3 based on an alignment of the THOC6 sequence (GenBank BC003118) with the genomic sequence (GRCh37).
In 2 sets of sisters from related Dariusleut Hutterite families with Beaulieu-Boycott-Innes syndrome (BBIS; 613680), a neurodevelopmental disorder, Beaulieu et al. (2013) identified a homozygous missense mutation in the THOC6 gene (G46R; 615403.0001). The mutation, which was found by Sanger sequencing followed by exome sequencing, segregated with the disorder in the family and was not found in the NHLBI Exome Variant Server and dbSNP databases, in 435 control exomes, or in 150 controls from the general population. The variant was seen in the heterozygous state in 3% of 92 Dariusleut controls and in 2% of 120 Lehrerleut controls. It was not present in 500 Schmiedeleut controls. In vitro functional expression studies showed that the mutation caused abnormal intracellular localization; knockdown of THOC6 in HeLa cells caused an increase in apoptosis. No THOC6 mutations were found in 140 female patients with intellectual disability and microcephaly.
In a 4-year old Saudi boy with BBIS, born to first cousins once removed, Anazi et al. (2016) identified a homozygous nonsense mutation in the THOC6 gene (R87X; 615403.0002). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family.
In 3 unrelated patients from France, Iran, and the U.S. with BBIS, Amos et al. (2017) identified homozygous or compound heterozygous mutations in the THOC6 gene (615403.0002-615403.0006). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing.
In an Italian girl with BBIS, Accogli et al. (2018) identified compound heterozygosity for 2 loss-of-function mutations in the THOC6 gene (615403.0007-615403.0008). The mutations were found by trio exome sequencing and confirmed by Sanger sequence. Each parent was heterozygous for one of the mutations.
Mattioli et al. (2019) used trio exome sequencing to evaluate 2 patients with BBIS. In the first patient, the authors identified homozygosity for a rare haplotype that included 3 amino acid changes (W100R, V234L, G275D; 615403.0009) in the THOC6 gene due to maternal uniparental disomy of chromosome 16, and in the second patient, they identified compound heterozygosity for the same haplotype, inherited from the mother, and a previously reported missense mutation (G190E; 615403.0005), inherited from the father. Both the triple mutant and G190E variants changed the physiologic localization of the THOC6 protein from its normal nuclear location to an abnormal cytosolic localization as well as its interaction with 2 THO subunits, THOC1 (606930) and THOC5 (612733). Two of the amino acid changes (W100R and G275D) from the 3-variant haplotype were predicted on their own to be deleterious according to most programs used, possibly resulting in pathogenicity of the haplotype. The W100R variant was predicted to be most pathogenic because it alters a tryptophan located in a WD-repeat domain, which is usually implicated in multiprotein assembly and interaction. The W100R variant was the only one of the 3 in the haplotype that on its own affected the nuclear localization of THOC6.
In zebrafish, Beaulieu et al. (2013) found that the Thoc6 ortholog was present during embryonic neurodevelopment. The gene was highly expressed in the developing midbrain and the eyes at 24 hours postfertilization, and later became restricted to the posterior part of the midbrain and the midbrain-hindbrain boundary.
In 2 sets of sisters from related Dariusleut Hutterite families with Beaulieu-Boycott-Innes syndrome (BBIS; 613680), Beaulieu et al. (2013) identified a homozygous c.136G-A transition in the THOC6 gene, resulting in a gly46-to-arg (G46R) substitution at a highly conserved residue. The mutation, which was found by Sanger sequencing followed by exome sequencing, segregated with the disorder in the family and was not found in the NHLBI Exome Variant Server and dbSNP databases, in 435 control exomes, or in 150 controls from the general population. The variant was seen in heterozygous state in 3% of 92 Dariusleut controls and in 2% of 120 Lehrerleut controls. It was not present in 500 Schmiedeleut controls. The disorder was characterized by delayed development, moderate intellectual disability, and dysmorphic facial features. Variable developmental anomalies, such as cardiac and renal defects, were also present. In HeLa cells, wildtype THOC6 showed a speckled nuclear localization, whereas mutant G46R THOC6 was confined to the cytoplasm, indicating that the mutation caused impaired intracellular localization. Knockdown of THOC6 in HeLa cells by siRNA resulted in increased apoptosis.
In a 4-year-old Saudi boy with Beaulieu-Boycott-Innes syndrome (BBIS; 613680), born to first cousins once removed, Anazi et al. (2016) identified homozygosity for a c.259C-T transition (c.259C-T, NM_001142350.2) in the THOC6, resulting in an arg87-to-ter (R87X) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family.
In an 18-year-old woman from the U.S. with BBIS, who was born to nonconsanguineous parents, Amos et al. (2017) identified compound heterozygous mutations in the THOC6 gene: R87X and a thr250-to-pro (T250P; 615403.0006) substitution. The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing.
In a 7-year-old boy, born to consanguineous Iranian parents, with Beaulieu-Boycott-Innes syndrome (BBIS; 613680), Amos et al. (2017) identified homozygosity for a c.611A-C transversion (c.611A-C, NM_024339.3) in the THOC6 gene, resulting in a gln204-to-pro (Q204P) substitution. The variant, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not present in the ExAC database. Protein modeling suggested that the mutation interrupts the normal structure and function of THOC6.
In a 6-year-old French boy, born to nonconsanguineous parents, with Beaulieu-Boycott-Innes syndrome (BBIS; 613680), Amos et al. (2017) identified compound heterozygous mutations in the THOC6 gene: a c.135C-A transversion (c.135C-A, NM_024339.3), resulting in a tyr45-to-ter (Y45X) substitution, and a c.569G-A transition, resulting in gly190-to-glu (G190E; 615403.0005) substitution. The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. The parents were each heterozygous for one of the mutations, which were present at low frequency in the ExAC database. Protein modeling suggested that the missense mutation interrupts the normal structure and function of THOC6.
For discussion of the c.569G-A transition (c.569G-A, NM_024339.3) in the THOC6 gene, resulting in a gly190-to-glu (G190E) substitution, that was found in compound heterozygous state in a patient with Beaulieu-Boycott-Innes syndrome (BBIS; 613680) by Amos et al. (2017), see 615403.0004.
In a female patient with BBIS, Mattioli et al. (2019) identified compound heterozygosity for mutations in the THOC6 gene: the G190E mutation inherited from her father, and a rare haplotype that included 3 amino acid changes (W100R, V234L, G275D; 615403.0009) inherited from her mother. Both the triple mutant and G190E variants changed the physiologic localization of the THOC6 protein from its normal nuclear location to an abnormal cytosolic localization as well as its interaction with 2 THO subunits, THOC1 (606930) and THOC5 (612733). Two of the amino acid changes (W100R and G275D) from the 3-variant haplotype were predicted on their own to be deleterious according to most programs used, possibly resulting in pathogenicity of the haplotype. The W100R variant was predicted to be most pathogenic because it alters a tryptophan located in a WD-repeat domain, which is usually implicated in multiprotein assembly and interaction. The W100R variant was the only one of the 3 in the haplotype that on its own affected the nuclear localization of THOC6.
In an 18-year-old woman from the U.S. with Beaulieu-Boycott-Innes syndrome (BBIS; 613680), who was born to nonconsanguineous parents, Amos et al. (2017) identified compound heterozygous mutations in the THOC6 gene: a c.748A-C transition (c.748A-C, NM_024339.3), resulting in a thr250-to-pro (T250P) substitution, and the previously identified R87X mutation (615403.0002). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. The nonsense mutation was inherited from the unaffected mother; the father could not be tested and the T250P mutation was presumed to be paternal or de novo. The T250P mutation was not found in the ExAC database, and protein modeling suggested that it interrupts the normal structure and function of THOC6.
In an Italian girl with Beaulieu-Boycott-Innes syndrome (BBIS; 613680), Accogli et al. (2018) identified compound heterozygous mutations in the THOC6 gene: a c.577C-T transition (c.577C-T, NM_024339) in exon 8, resulting in an arg193-to-ter (R193X) substitution, inherited from her mother, and a 2-bp deletion (c.792_793delCA; 615403.0008) in exon 11, resulting in a frameshift and a premature termination codon (Val264ValfsTer48), inherited from her father. The mutations were identified by trio exome sequencing and confirmed by Sanger sequencing. The R193X mutation was not found in any public databases. The 2-bp deletion was found in 1 of 246,156 alleles in the gnomAD database, with a frequency of .4062x10(-5).
For discussion of the 2-bp deletion (c.792_793delCA, NM_024339) in the THOC6 gene that was found in compound heterozygous state in an Italian girl with Beaulieu-Boycott-Innes syndrome (BBIS; 613680) by Accogli et al. (2018), see 615403.0007.
In a boy with Beaulieu-Boycott-Innes syndrome (BBIS; 613680), Mattioli et al. (2019) identified homozygosity for a rare haplotype including 3 amino acid changes (W100R, V234L, G275D) in the THOC6 gene due to maternal uniparental disomy of chromosome 16. The mutation was found by trio exome sequencing. The triple mutant changed the physiologic localization of the THOC6 protein from its normal nuclear location to an abnormal cytosolic localization as well as its interaction with 2 THO subunits, THOC1 (606930) and THOC5 (612733). Two of the amino acid changes (W100R and G275D) were predicted on their own to be deleterious according to most programs used, possibly resulting in pathogenicity of the haplotype. The W100R variant was predicted to be most pathogenic because it alters a tryptophan located in a WD-repeat domain, which is usually implicated in multiprotein assembly and interaction. The W100R variant was the only one of the 3 in the haplotype that on its own affected the nuclear localization of THOC6. Another patient reported by Mattioli et al. (2019) was compound heterozygous for the 3-amino acid haplotype and a missense mutation (G190E; 615403.0005).
Accogli, A., Scala, M., Calcagno, A., Castello, R., Torella, A., Musacchia, F., Allegri, A. M. E., Mancardi, M. M., Maghnie, M., Severino, M., Telethon Undiagnosed Diseases Program, Nigro, V., Capra, V. Novel CNS malformations and skeletal anomalies in a patient with Beaulieu-Boycott-Innes syndrome. Am. J. Med. Genet. 176A: 2835-2840, 2018. [PubMed: 30238602] [Full Text: https://doi.org/10.1002/ajmg.a.40534]
Amos, J. S., Huang, L., Thevenon, J., Kariminedjad, A., Beaulieu, C. L., Masurel-Paulet, A., Najmabadi, H., Fattahi, Z., Beheshtian, M., Tonekaboni, S. H., Tang, S., Helbig, K. L., Alcaraz, W., Riviere, J.-B., Faivre, L., Innes, A. M., Lebel, R. R., Boycott, K. M., Care4Rare Canada Consortium. Autosomal recessive mutations in THOC6 cause intellectual disability: syndrome delineation requiring forward and reverse phenotyping. Clin. Genet. 91: 92-99, 2017. [PubMed: 27102954] [Full Text: https://doi.org/10.1111/cge.12793]
Anazi, S., Alshammari, M., Moneis, D., Abouelhoda, M., Ibrahim, N., Alkuraya, F. S. Confirming the candidacy of THOC6 in the etiology of intellectual disability. (Letter) Am. J. Med. Genet. 170A: 1367-1369, 2016. [PubMed: 26739162] [Full Text: https://doi.org/10.1002/ajmg.a.37549]
Beaulieu, C. L., Huang, L., Innes, A. M., Akimenko, M.-A., Puffenberger, E. G., Schwartz, C., Jerry, P., Ober, C., Hegele, R. A., McLeod, D. R., Schwartzentruber, J., Majewski, J., Bulman, D. E., Parboosingh, J. S., Boycott, K. M. Intellectual disability associated with a homozygous missense mutation in THOC6. Orphanet J. Rare Dis. 8: 62, 2013. Note: Electronic Article. [PubMed: 23621916] [Full Text: https://doi.org/10.1186/1750-1172-8-62]
Hartz, P. A. Personal Communication. Baltimore, Md. 9/6/2013.
Masuda, S., Das, R., Cheng, H., Hurt, E., Dorman, N., Reed, R. Recruitment of the human TREX complex to mRNA during splicing. Genes Dev. 19: 1512-1517, 2005. [PubMed: 15998806] [Full Text: https://doi.org/10.1101/gad.1302205]
Mattioli, F., Isidor, B., Abdul-Rahman, O., Gunter, A., Huang, L., Kumar, R., Beaulieu, C., Gecz, J., Innes, M., Mandel, J.-L., Piton, A. Clinical and functional characterization of recurrent missense variants implicated in THOC6-related intellectual disability. Hum. Molec. Genet. 28: 952-960, 2019. [PubMed: 30476144] [Full Text: https://doi.org/10.1093/hmg/ddy391]