Alternative titles; symbols
HGNC Approved Gene Symbol: THAP11
Cytogenetic location: 16q22.1 Genomic coordinates (GRCh38) : 16:67,842,320-67,844,195 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16q22.1 | ?Methylmalonic aciduria and homocystinuria, cblL type | 620940 | Autosomal recessive | 3 |
| Spinocerebellar ataxia 51 | 620947 | Autosomal dominant | 3 |
The THAP11 gene encodes a transcription factor that forms a complex with HCFC1 (300019) to regulate the transcription of MMACHC (609831), an enzyme involved in cobalamin metabolism. The THAP11/HCFC1 complex is also involved in the regulation of ribosome biogenesis during embryonic development (summary by Quintana et al., 2017; Chern et al., 2022).
By searching databases, Roussigne et al. (2003) identified several proteins containing a THAP domain, including THAP11. The THAP domain includes a C2CH signature, an AVPTIF box, and several other conserved amino acids. It appears to be restricted to animal proteins and shows similarity to a DNA-binding domain of Drosophila P element transposase. The deduced 314-amino acid THAP11 protein contains an N-terminal THAP domain, followed by a central 30-amino acid polyglutamine tract.
By bioinformatic analysis, Dehaene et al. (2020) found that the 12 human THAP proteins share a structurally similar THAP domain that shows considerable variability in size, ranging from 213 to 903 amino acids. Most THAP proteins, including THAP11, contain an HCF1 (HCFC1)-binding motif (HBM) and a coiled-coil domain.
Dejosez et al. (2008) found that mouse Thap11, which they designated Ronin, was expressed primarily during the earliest stages of embryonic development, and that its deficiency produced periimplantational lethality and defects in the inner cell mass. Conditional knockout of Ronin prevented growth of embryonic stem (ES) cells, while forced expression of Ronin allowed ES cells to proliferate without differentiation under conditions that normally would not promote self-renewal. Ectopic expression also partly compensated for Oct4 (POU5F1; 164177) knockdown. Dejosez et al. (2008) found that Ronin bound directly to Hcf1, a key transcriptional regulator. They concluded that Ronin is an essential factor underlying embryogenesis and ES cell pluripotency.
By immunoprecipitation analysis, Dehaene et al. (2020) showed that THAP11 formed homodimers, likely via its coiled-coil domain. THAP11 also interacted with HCF1, with the interaction mediated by the HBM motif of THAP11 and the Kelch domain of HCF1.
Tan et al. (2023) identified the THAP11 gene within a candidate region mapping to chromosome 16q22.1.
Methylmalonic Aciduria and Homocystinuria, cblL Type
In a boy, born of Moroccan parents, with methylmalonic aciduria cblL type (MAHCL; 620940) without homocysteinuria, Quintana et al. (2017) identified a homozygous missense mutation in the THAP11 gene (F80L; 609119.0001). The mutation, which was found by direct sequencing of the THAP11 gene in patient cells, was not present in public databases, including gnomAD. Parental DNA was not available, so familial segregation studies could not be performed. Quintana et al. (2017) studied the THAP11 gene based on the known interaction between THAP11 and HCFC1 (300019), which is mutated in MAHCX (309541). Although complementation studies were consistent with a biochemical diagnosis of cblC (277400), mutation in the MMACHC gene (609831) was excluded. RNA-seq analysis of patient fibroblasts showed downregulation of several genes, including TMOD2 (602928) and MMACHC, the latter of which most likely caused the aberrant cobalamin metabolism. The transcriptome clustered in the same clade found in patients with mutations in the HCFC1 gene. Retroviral transduction of MMACHC into patient THAP11-mutant fibroblasts corrected the cobalamin-related biochemical abnormalities. The findings, including results of studies in zebrafish, indicated that THAP11 and HCFC1 coregulate an overlapping set of genes which play a role in the phenotype of both MAHCL and MAHCX.
Spinocerebellar Ataxia 51
In 5 affected members of a large multigenerational Chinese family (family 1) with spinocerebellar ataxia-51 (SCA51; 620947), Tan et al. (2023) identified a heterozygous (CAG)n trinucleotide repeat expansion in exon 1 of the THAP11 gene (609119.0002). The mutation, which was found by a combination of linkage analysis and long-range sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The number of expanded CAG repeats in 4 of the symptomatic patients with onset in adulthood ranged from 45 to 55, whereas the repeat was 100 in the 1 patient with onset at 4 years of age. In addition, there were 6 asymptomatic ('preataxic') individuals in family 1 who carried expanded CAG repeats between 54 to 59, suggesting that they may develop the disease later. A heterozygous expanded repeat of 47 was identified in another family (family 2) in which the symptomatic son (proband) had onset at age 16 years, but his 43-year-old asymptomatic ('preataxic') father also carried an expanded repeat of 47. The repeat number in unaffected individuals ranged from 20 to 34, with the most common size being 28 and 29. There was a strong correlation between the size of the (CAG)n repeat and earlier symptom onset, indicating genetic anticipation. Skin fibroblasts from 3 patients in family 1 and in vitro cellular studies showed abnormal cytoplasmic THAP11-containing polyQ aggregates, intracellular p62 (SQSTM1; 601530) aggregates, and decreased viability compared to controls, illustrating the toxic effects of mutant THAP11 proteins.
Hsiao et al. (2024) did not find expanded trinucleotide repeats in the THAP11 gene among 385 Taiwanese patients of Han Chinese descent with cerebellar ataxia, indicating that the THAP11 repeat expansion is rare. The authors noted they were unable to confirm the findings of Tan et al. (2023).
Quintana et al. (2017) found that thap11-null zebrafish embryos had severe craniofacial abnormalities, including defective development of Meckel cartilage. These defects were restored with wildtype THAP11. Thap11-null zebrafish also showed structural brain anomalies associated with abnormal acetylated tubulin and reduced axons, as well as increased numbers of SOX2 (184429) neural progenitor cells, suggesting impaired neuronal differentiation. Overexpression of THAP11 mRNA also increased the number of SOX2-positive cells in certain brain regions. The results indicated that changes in the level of thap11 expression during brain development can alter the fate of neural precursors. In contrast, expression of the human F80L mutation (609119.0001) significantly decreased the number of SOX2-positive neural precursor cells in the developing brain, with a bias toward neuronal differentiation. Similar findings were observed in hcfc1-null zebrafish.
Chern et al. (2022) found that almost all mutant mice that were homozygous for the F80L mutation (609118.0001) died prior to weaning. Out of 260 mutant mice, only 1 survived to about 1 month of age and was runted. Studies of pregnant dams indicated that the homozygous mutant pups died from an inability to breathe, without brainstem, lung, or diaphragm defects. Mutant mice showed developmental brain defects and disrupted astrogliogenesis. Additional features included myocardial abnormalities, anemia, and craniofacial defects. F80L Thap11 mutant transcripts were increased in mutant mouse brain, but protein levels were decreased, suggesting instability of the mutant protein. Although mutant F80L Thap11 was still able to bind to Hcfc1, it likely was unable to bind to DNA, causing impaired function. There was a dramatic reduction in Mmachc RNA and protein expression associated with decreased cobalamin coenzymes MeCbl and AdoCbl and decreased functional activity of MTR (156570) and MUT (609058). Similar findings were observed in hemizygous male mice carrying the HCFC1 mutation A115V (300019.0003). RNA-seq analysis showed dysregulation of genes involved in ribosome biogenesis and there was abnormal protein translation; the authors concluded that THAP11 and HCFC1 mutations cause a ribosomopathy.
In a boy, born of Moroccan parents, with methylmalonic aciduria (MAHCL; 620940), Quintana et al. (2017) identified a homozygous c.240C-G transversion (c.240C-G, NM_020457.2) in the THAP11 gene, resulting in a phe80-to-leu (F80L) substitution at a highly conserved residue in the DNA-binding domain. The mutation, which was found by direct sequencing of the THAP11 gene in patient cells, was not present in public databases, including gnomAD. Parental DNA was not available, so familial segregation studies could not be performed. Quintana et al. (2017) studied the THAP11 gene based on the known interaction between THAP11 and HCFC1 (300019), which is mutated in MAHCX (309541). RNA-seq analysis of patient fibroblasts showed downregulation of several genes, including TMOD2 (602928) and MMACHC (609831), the latter of which most likely caused the aberrant cobalamin metabolism. Retroviral transduction of MMACHC into patient THAP11 mutant fibroblasts corrected the cobalamin-related biochemical abnormalities. The patient presented at 2 months of age with myoclonic seizures followed by profound developmental delay with encephalopathy. Metabolic studies showed mild methylmalonic aciduria without homocysteinuria. Although complementation studies were consistent with a biochemical diagnosis of cblC (277400), mutation in the MMACHC gene was excluded. The patient died at 10 years of age.
Dehaene et al. (2020) found that HEK293 cell lines homozygous for the THAP11 F80L mutation grew more slowly than wildtype, suggesting that THAP11 was important for sustaining cell proliferation. The F80L mutation selectively affected promoter binding by THAP11, having more deleterious effects on a subset of THAP11 targets, resulting in altered patterns of gene expression. In particular, F80L had a strong effect on association of THAP11 with the MMACHC promoter, leading to a decrease in MMACHC transcription and, ultimately, cobalamin disorder.
In 5 affected members of a large multigenerational Chinese family (family 1) with spinocerebellar ataxia-51 (SCA51; 620947), Tan et al. (2023) identified a heterozygous trinucleotide (CAG) repeat expansion in exon 1 of the THAP11 gene. The mutation, which was found by a combination of linkage analysis and long-range sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The number of expanded CAG repeats in 4 of the symptomatic patients with onset in adulthood ranged from 45 to 55, whereas the repeat was 100 in the 1 patient with onset at 4 years of age. In addition, there were 6 asymptomatic ('preataxic') individuals in family 1 who carried expanded CAG repeats between 54 to 59, suggesting that they may develop the disease later. Pathogenic expanded repeats in other SCA-related genes were excluded. A heterozygous expanded repeat of 47 was identified in another family (family 2) in which the symptomatic son (proband) had onset at age 16 years, but his 43-year-old asymptomatic ('preataxic') father also carried an expanded repeat of 47. The repeat number in unaffected individuals ranged from 20 to 34, with the most common size being 28 and 29. There was a strong correlation between the size of the (CAG)n repeat and earlier symptom onset, indicating genetic anticipation. Tan et al. (2023) also identified (CAA)n interruptions within the (CAG)n repeat expansion that ranged from 5 to 6 in healthy individuals, but was decreased to 3 repeats in patients. Skin fibroblasts from 3 patients in family 1 and in vitro cellular studies in transfected neuro-2a and HEK293 cells showed abnormal cytoplasmic THAP11-containing polyQ aggregates, autophagic vacuoles, intracellular p62 (SQSTM1; 601530) aggregates, and decreased viability compared to controls, illustrating the toxic effects of mutant THAP11 proteins.
Chern, T., Achilleos, A., Tong, X., Hill, M. C., Saltzman, A. B., Reineke, L. C., Chaudhury, A., Dasgupta, S. K., Redhead, Y., Watkins, D., Neilson, J. R., Thiagarajan, P., Green, J. B. A., Malovannaya, A., Martin, J. F., Rosenblatt, D. S., Poche, R. A. Mutations in Hcfc1 and Ronin result in an inborn error of cobalamin metabolism and ribosomopathy. Nature Commun. 13: 134, 2022. [PubMed: 35013307] [Full Text: https://doi.org/10.1038/s41467-021-27759-7]
Dehaene, H., Praz, V., Lhote, P., Lopes, M., Herr, W. THAP11F80L cobalamin disorder-associated mutation reveals normal and pathogenic THAP11 functions in gene expression and cell proliferation. PLoS One 15: e0224646, 2020. [PubMed: 31905202] [Full Text: https://doi.org/10.1371/journal.pone.0224646]
Dejosez, M., Krumenacker, J. S., Zitur, L. J., Passeri, M., Chu, L.-F., Songyang, Z., Thomson, J. A., Zwaka, T. P. Ronin is essential for embryogenesis and the pluripotency of mouse embryonic stem cells. Cell 133: 1162-1174, 2008. Note: Erratum: Cell 134: 692 only, 2008. [PubMed: 18585351] [Full Text: https://doi.org/10.1016/j.cell.2008.05.047]
Hsiao, C.-T., Liao, N.-Y., Liao, Y.-C., Lee, Y.-C. THAP11 CAG repeat expansion is rare or absent in the Taiwanese cohort with cerebellar ataxia. Mov. Disord. 39: 924-925, 2024. [PubMed: 38757579] [Full Text: https://doi.org/10.1002/mds.29800]
Quintana, A. M., Yu, H.-C., Brebner, A., Pupavac, M., Geiger, E. A., Watson, A., Castro, V. L., Cheung, W., Chen, S.-H., Watkins, D., Pastinen, T., Skovby, F., Appel, B., Rosenblatt, D. S., Shaikh, T. H. Mutations in THAP11 cause an inborn error of cobalamin metabolism and developmental abnormalities. Hum. Molec. Genet. 26: 2838-2849, 2017. [PubMed: 28449119] [Full Text: https://doi.org/10.1093/hmg/ddx157]
Roussigne, M., Kossida, S., Lavigne, A.-C., Clouaire, T., Ecochard, V., Glories, A., Amalric, F., Girard, J.-P. The THAP domain: a novel protein motif with similarity to the DNA-binding domain of P element transposase. Trends Biochem. Sci. 28: 66-69, 2003. [PubMed: 12575992] [Full Text: https://doi.org/10.1016/S0968-0004(02)00013-0]
Tan, D., Wei, C., Chen, Z., Huang, Y., Deng, J., Li, J., Liu, Y., Bao, X., Xu, J., Hu, Z., Wang, S., Fan, Y., and 13 others. CAG repeat expansion in THAP11 is associated with a novel spinocerebellar ataxia. Mov. Disord. 38: 1282-1293, 2023. [PubMed: 37148549] [Full Text: https://doi.org/10.1002/mds.29412]