Alternative titles; symbols
HGNC Approved Gene Symbol: HCFC1
Cytogenetic location: Xq28 Genomic coordinates (GRCh38): X:153,947,557-153,971,818 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xq28 | Methylmalonic aciduria and homocysteinemia, cblX type | 309541 | X-linked recessive | 3 |
The HCFC1 gene encodes a chromatin-associated transcriptional regulator (summary by Huang et al., 2012).
From the G+C-rich isochore located in Xq28 between DXS52 and the factor VIII gene (F8; 300841), Frattini et al. (1994) isolated a transcript mapping about 50 kb telomeric from the AVPR2 gene (300538) in a 180-kb contig containing the L1CAM gene at its centromeric end. The sequence from a human fetal brain library was found to be identical to that of HCF1 (host cell factor C1) that activates herpes simplex virus VP16 transactivator protein for association with the octamer motif-binding protein Oct1 (164175), identified by Wilson et al. (1993). The gene was expressed in a ubiquitous pattern, and a larger transcript of approximately 10 kb was present in all the tissues tested, whereas an alternatively spliced RNA of approximately 8.0 kb was present in muscle and heart tissues. Other findings suggested that alternative mRNA processing can partly contribute to the diversity of the polypeptide HCF1 family in a subset of tissues.
Frattini et al. (1996) demonstrated that the mouse Hcfc1 protein shows a very high degree of conservation with 19-amino acid motifs located in the middle of the human protein. This suggests an important function for these repeats.
By genomic sequence analysis, Frattini et al. (1994) demonstrated that the HCFC1 transcript is assembled from 26 exons spread over approximately 24 kb.
By fluorescence in situ hybridization and somatic cell hybrid analysis, Wilson et al. (1995) mapped the HCFC1 gene to Xq28. YAC and cosmid mapping localized the HCFC1 gene within 100 kb distal of the V2R gene and adjacent to the renin-binding protein gene (312420).
Faranda et al. (1995) found that the 3-prime end of HCFC1 lies 2,763-bp upstream from the 3-prime end of the renin-binding protein gene (312420). Thus both genes are transcribed in the same direction, from the telomere to the centromere.
Frattini et al. (1996) found that the mouse gene maps to a region syntenic to Xq28 and, as in human, is in close proximity to the renin-binding protein gene, in a 100-kb region also including L1cam and vasopressin receptor type 2 genes.
Wilson et al. (1995) found that HCF transcripts and protein are most abundant in fetal and placental tissues and cell lines, suggesting a role in cell proliferation. In adults, HCF protein is abundant in the kidney, but not in the brain, a site of latent herpes simplex virus (HSV) infection and a site where HCF levels may influence progression of HSV infection.
Zoppe et al. (1996) reported the complete sequence of the HCFC1 gene, including 2 kb of the 5-prime flanking region and 5.9 kb of the first intron. In addition to the detection of many putative binding sites for known DNA binding proteins, a highly conserved 17-bp sequence was found to be present 6 times at regular intervals in the 5-prime region of the gene. This motif is capable of binding the transcription factor Yin/Yang 1 (YY1; 600013) as well as another unidentified factor, suggesting that HCFC1 expression is regulated by the interaction of these factors.
Using a yeast interaction screen, Mahajan et al. (2002) showed that human HPIP (HCFC1R1; 618818) interacted with the beta-propeller domain of HCF1. HPIP shuttled between the nucleus and cytoplasm in a CRM1 (602559)-dependent manner, and interaction of HCF1 with HPIP allowed HCF1 to be exported from the nucleus to the cytoplasm.
Using chromatin immunoprecipitation, PCR, coimmunoprecipitation, and reporter analyses, Liang et al. (2009) found that infection by the alpha-herpesviruses, HSV and varicella zoster virus (VZV), resulted in rapid accumulation of chromatin bearing repressive histone H3 lys9 (H3K9) methylation. Expression of viral immediate early (IE) genes required HCF1 to recruit LSD1 (KDM1A; 609132) to viral immediate early promoters. Depletion of LSD1 or dose-dependent inhibition of LSD1 with monoamine oxidase inhibitors (MAOIs) resulted in accumulation of repressive chromatin and a block to viral gene expression. HCF1, together with SET1 (SETD1A; 611052) and MLL1 (159555), coordinated modulation of repressive H3K9 methylation levels with addition of activating H3K4 trimethylation marks. Liang et al. (2009) concluded that LSD1 prevents accumulation of H3K9 methylation and allows productive infection by both alpha-herpesviruses. They proposed that the dependence of viral pathogens on the host-cell chromatin machinery highlights a potential therapeutic intervention, and that targeting LSD1 with widely used MAOIs may prevent viral latency and reactivation.
Huang et al. (2012) found high expression of the Hcfc1 gene during murine brain development, consistent with a role in proliferative cells. Expression decreased during embryogenesis, but was still present during postnatal development, suggesting a role in postmitotic cells as well. Overexpression of the Hcfc1 gene in cultured murine neuronal stem cells resulted in a significant reduction of cells in the proliferative stage, promotion of cell cycle exit, and increased production of astrocytes. Overexpression of the Hcfc1 gene in embryonic hippocampal neurons caused a reduction in neurite growth, a reduction in the degree of neurite arborization, and increased neuronal death. The findings suggested that HCFC1 is a potent regulator of embryonic neural development.
HCFC1, a transcriptional coregulator of human cell cycle progression, undergoes proteolytic maturation in which any of 6 repeated sequences is cleaved by the nutrient-responsive glycosyltransferase, O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT; 300255). Lazarus et al. (2013) reported that the tetratricopeptide repeat domain of OGT binds the carboxyl terminal portion of an HCFC1 proteolytic repeat such that the cleavage region lies in the glycosyltransferase active site above uridine diphosphate-GlcNAc. The conformation is similar to that of a glycosylation-competent peptide substrate. Cleavage occurs between cysteine and glutamate residues and results in a pyroglutamate product. Conversion of the cleavage site glutamate into serine converts an HCFC1 proteolytic repeat into a glycosylation substrate. Lazarus et al. (2013) concluded that protein glycosylation and HCFC1 cleavage occur in the same active site.
In affected members of a family with X-linked intellectual developmental disorder-3 (XLID3; 309541) originally reported by Gedeon et al. (1991), Huang et al. (2012) identified a 455A-G transition in the 5-prime untranslated region of the HCFC1 gene (300019.0001) that disrupted a binding site for the transcription factor YY1. HCFC1 mRNA was 1.6-fold higher in patient lymphoblastoid cells compared to controls. Microarray data of gene expression showed deregulation of multiple genes involved in mitochondrial function or biogenesis in patients with MRX3 compared to controls. Exome sequencing of additional probands from families with X-linked mental retardation found a missense mutation in the HCFC1 gene (S225N; 300019.0002) in 1 proband that segregated with the disorder in that family. Two additional variants in the HCFC1 gene were identified in 2 more probands, but each proband also carried a mutation in another gene (ZMYM3, 300061 and MED13, 300118, respectively), so the contribution of the HCFC1 change to the phenotype could not adequately be determined.
In 14 unrelated males with X-linked intellectual developmental disorder with a cobalamin disorder identified through laboratory studies (MHACX; 309541), Yu et al. (2013) identified 5 different hemizygous missense mutations in the HCFC1 gene (see, e.g., 300019.0003-300019.0005). Nine of the patients carried the same mutation (A115V; 300019.0003). All mutations occurred at highly conserved residues in 2 of the 5 N-terminal kelch domains. The mutation in the first patient was found by exome sequencing, and the subsequent mutations were found by HCFC1 screening of 17 males with a similar disorder and laboratory findings. All patients had severely delayed psychomotor development apparent in infancy and associated with failure to thrive, mental retardation, and intractable epilepsy. Many had microcephaly and/or choreoathetosis. Complementation studies suggested cblC (277400), but mutations were not found in the MMACHC gene (609831). Fibroblasts from 2 patients showed decreased mRNA and protein levels of MMACHC, whereas mRNA and protein levels of HCFC1 were normal. Knockdown of HCFC1 in HEK293 cells downregulated MMACHC. These finding suggested that mutations in HCFC1 inhibit its function in the transcriptional activation of MMACHC, and showed that perturbation of transcription can cause an inborn error of metabolism.
In affected members of a family with X-linked intellectual developmental disorder-3 (XLID3; 309541) originally reported by Gedeon et al. (1991), Huang et al. (2012) identified a 455A-G transition in the 5-prime untranslated region of the HCFC1 gene within the S2 binding site for the transcription factor YY1 (600013). HCFC1 mRNA was 1.6-fold higher in patient lymphoblastoid cells compared to controls, and the 455A-G variant was shown to completely abolish YY1 binding in HEK293 T cells. Overexpression of the Hcfc1 gene in cultured murine neuronal stem cells resulted in a significant reduction of cells in the proliferative stage, promotion of cell-cycle exit, and increased production of astrocytes. Overexpression of the Hcfc1 gene in embryonic hippocampal neurons caused a reduction in neurite growth, a reduction in the degree of neurite arborization, and increased neuronal death. The findings suggested that HCFC1 is a potent regulator of embryonic neural development. Biochemical studies were not reported in this family.
By exome sequencing of a proband from a family with intellectual developmental disorder (XLID3; 309541), Huang et al. (2012) identified a 674G-A transition in the HCFC1 gene, resulting in a ser225-to-asn (S225N) substitution at a highly conserved residue in one of the Kelch domains. The mutation segregated with the disorder in 3 additional affected male family members. Biochemical studies were not reported in this family.
In 9 unrelated males with methylmalonic aciduria and homocystinuria, cblX type (MAHCX; 309541), Yu et al. (2013) identified a hemizygous c.344C-T transition in exon 3 of the HCFC1 gene, resulting in an ala115-to-val (A115V) substitution at a highly conserved residue in the second kelch motif. The mutation in the first patient was found by exome sequencing and confirmed by Sanger sequencing; the mutation was present in his unaffected mother. The variant was not found in the dbSNP, NHLBI Exome Variant Server, or 1000 Genomes Project databases. Sanger sequencing did not find the variant in 50 control individuals of European descent, but it was found in 1 female individual among 50 control individuals of African American descent. The patients had severely delayed psychomotor development apparent in infancy and intractable seizures associated in most cases with increased plasma homocysteine and increased serum methylmalonic acid.
In 2 unrelated boys with methylmalonic aciduria and homocystinuria, cblX type (MAHCX; 309541), Yu et al. (2013) identified a hemizygous c.218C-T transition in the HCFC1 gene, resulting in an ala73-to-val (A73V) substitution at a highly conserved residue in the first kelch motif. The patients had severely delayed psychomotor development apparent in infancy and intractable seizures.
In a boy with methylmalonic aciduria and homocystinuria, cblX type (MAHCX; 309541), Yu et al. (2013) identified a hemizygous c.217G-A transition in the HCFC1 gene, resulting in an ala73-to-thr (A73T) substitution at a highly conserved residue in the first kelch motif. The patient had severely delayed psychomotor development apparent in infancy, intractable seizures, and failure to thrive.
Faranda, S., Frattini, A., Vezzoni, P. The human genes encoding renin-binding protein and host cell factor are closely linked in Xq28 and transcribed in the same direction. Gene 155: 237-239, 1995. [PubMed: 7721097] [Full Text: https://doi.org/10.1016/0378-1119(94)00810-f]
Frattini, A., Chatterjee, A., Faranda, S., Sacco, M. G., Villa, A., Herman, G. E., Vezzoni, P. The chromosome localization and the HCF repeats of the human host cell factor gene (HCFC1) are conserved in the mouse homologue. Genomics 32: 277-280, 1996. [PubMed: 8833156] [Full Text: https://doi.org/10.1006/geno.1996.0116]
Frattini, A., Faranda, S., Redolfi, E., Zucchi, I., Villa, A., Patrosso, M. C., Strina, D., Susani, L., Vezzoni, P. Genomic organization of the human VP16 accessory protein, a housekeeping gene (HCFC1) mapping to Xq28. Genomics 23: 30-35, 1994. [PubMed: 7829097] [Full Text: https://doi.org/10.1006/geno.1994.1455]
Gedeon, A., Kerr, B., Mulley, J., Turner, G. Localisation of the MRX3 gene for non-specific X linked mental retardation. J. Med. Genet. 28: 372-377, 1991. [PubMed: 1870093] [Full Text: https://doi.org/10.1136/jmg.28.6.372]
Huang, L., Jolly, L. A., Willis-Owen, S., Gardner, A., Kumar, R., Douglas, E., Shoubridge, C., Wieczorek, D., Tzschach, A., Cohen, M., Hackett, A., Field, M., Froyen, G., Hu, H., Haas, S. A., Ropers, H.-H., Kalscheuer, V. M., Corbett, M. A., Gecz, J. A noncoding, regulatory mutation implicates HCFC1 in nonsyndromic intellectual disability. Am. J. Hum. Genet. 91: 694-702, 2012. [PubMed: 23000143] [Full Text: https://doi.org/10.1016/j.ajhg.2012.08.011]
Lazarus, M. B., Jiang, J., Kapuria, V., Bhuiyan, T., Janetzko, J., Zandberg, W. F., Vocadlo, D. J., Herr, W., Walker, S. HCF-1 is cleaved in the active site of O-GlcNAc transferase. Science 342: 1235-1239, 2013. [PubMed: 24311690] [Full Text: https://doi.org/10.1126/science.1243990]
Liang, Y., Vogel, J. L., Narayanan, A., Peng, H., Kristie, T. M. Inhibition of the histone demethylase LSD1 blocks alpha-herpesvirus lytic replication and reactivation from latency. Nature Med. 15: 1312-1317, 2009. [PubMed: 19855399] [Full Text: https://doi.org/10.1038/nm.2051]
Mahajan, S. S., Little, M. M., Vazquez, R., Wilson, A. C. Interaction of HCF-1 with a cellular nuclear export factor. J. Biol. Chem. 277: 44292-44299, 2002. [PubMed: 12235138] [Full Text: https://doi.org/10.1074/jbc.M205440200]
Wilson, A. C., LaMarco, K., Peterson, M. G., Herr, W. The VP16 accessory protein HCF is a family of polypeptides processed from a large precursor protein. Cell 74: 115-125, 1993. [PubMed: 8392914] [Full Text: https://doi.org/10.1016/0092-8674(93)90299-6]
Wilson, A. C., Parrish, J. E., Massa, H. F., Nelson, D. L., Trask, B. J., Herr, W. The gene encoding the VP16-accessory protein HCF (HCFC1) resides in human Xq28 and is highly expressed in fetal tissues and the adult kidney. Genomics 25: 462-468, 1995. [PubMed: 7789979] [Full Text: https://doi.org/10.1016/0888-7543(95)80046-o]
Yu, H.-C., Sloan, J. L., Scharer, G., Brebner, A., Quintana, A. M., Achilly, N. P., Manoli, I., Coughlin, C. R., II, Geiger, E. A., Schneck, U., Watkins, D., Suormala, T., Van Hove, J. L. K., Fowler, B., Baumgartner, M. R., Rosenblatt, D. S., Venditti, C. P., Shaikh, T. H. An X-linked cobalamin disorder caused by mutations in transcriptional coregulator HCFC1. Am. J. Hum. Genet. 93: 506-514, 2013. [PubMed: 24011988] [Full Text: https://doi.org/10.1016/j.ajhg.2013.07.022]
Zoppe, M., Frattini, A., Faranda, S., Vezzoni, P. The complete sequence of the host cell factor 1 (HCFC1) gene and its promoter: a role for YY1 transcription factor in the regulation of its expression. Genomics 34: 85-91, 1996. [PubMed: 8661027] [Full Text: https://doi.org/10.1006/geno.1996.0244]