Alternative titles; symbols
HGNC Approved Gene Symbol: HES7
Cytogenetic location: 17p13.1 Genomic coordinates (GRCh38) : 17:8,120,592-8,126,634 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17p13.1 | Spondylocostal dysostosis 4, autosomal recessive | 613686 | Autosomal recessive | 3 |
HES7 encodes a basic helix-loop-helix-Orange domain transcriptional repressor protein that is both a direct target of the Notch signaling pathway (see 190198) and part of a negative feedback mechanism required to attenuate Notch signaling (summary by Sparrow et al., 2008)
Bessho et al. (2001) cloned mouse Hes7 and, by EST database searching and PCR, obtained a cDNA encoding human HES7. The deduced mouse and human proteins contain 225 amino acids, and both have an N-terminal basic helix-loop-helix (bHLH) domain, a central 'orange' domain, and a conserved C-terminal WRPW sequence. Human and mouse HES7 are identical in the bHLH domain and share 90.7% amino acid identity overall. Compared with other mouse HES proteins, Hes7 is most similar to Hes5 (607348), particularly in the bHLH and orange domains. Northern blot analysis of day-9.5 mouse embryos detected a 1.0-kb Hes7 transcript.
Bessho et al. (2001) determined that mouse Hes7 contains 4 exons and spans about 3 kb.
Gross (2013) mapped the HES7 gene to chromosome 17p13.1 based on an alignment of the HES7 sequence (GenBank AB049064) with the genomic sequence (GRCh37).
Bessho et al. (2001) mapped the mouse Hes7 gene to chromosome 11, next to the Aloxe3 gene (607206).
By in situ hybridization of day-8.5 through day-12.0 mouse embryos, Bessho et al. (2001) found dynamic expression of Hes7 in the presomitic mesoderm (PSM). Transfection experiments determined that mouse Hes7 repressed transcription from N box- and E box-containing promoters. Hes7 also suppressed E47 (147141)-induced transcriptional activation. Promoter analysis indicated that mouse Hes7 expression was controlled by Notch signaling.
During somitogenesis, a pair of somites buds off from the PSM every 2 hours in mouse embryos, suggesting that somite segmentation is controlled by a biologic clock with a 2-hour cycle. Expression of Hes7, an effector of Notch signaling, follows a 2-hour oscillatory cycle controlled by negative feedback; it had been proposed that this is the molecular basis for the somite segmentation clock. To address the biologic importance of Hes7 instability, Hirata et al. (2004) generated mice expressing mutant Hes7 with a longer half-life but normal repressor activity. In these mice, somite segmentation and oscillatory expression became severely disorganized after a few normal cycles of segmentation. Hirata et al. (2004) simulated this effect mathematically using a direct autorepression model. Thus, instability of Hes7 is essential for sustained oscillation and for its function as a segmentation clock.
Diaz-Cuadros et al. (2020) showed that human and mouse PSM cells derived in vitro recapitulated the oscillations of the segmentation clock, as measured by expression of fluorescence-tagged HES7. Human PSM cells oscillated with a period 2 times longer than that of mouse cells (5 vs 2.5 hours, respectively), but were similarly regulated by FGF (see 131220), Wnt (see 606359), Notch, and YAP (YAP1; 606608) signaling. Single-cell RNA sequencing revealed that mouse and human PSM cells in vitro followed a developmental trajectory similar to that of mouse PSM cells in vivo. Furthermore, Diaz-Cuadros et al. (2020) demonstrated that FGF signaling controlled the phase and period of oscillations, expanding the role of this pathway beyond its classical interpretation in 'clock and wavefront' models.
Yoshioka-Kobayashi et al. (2020) established a live-imaging system in which a fluorescent reporter was fused to Hes7 to monitor synchronous oscillations in Hes7 expression in mouse PSM at single-cell resolution. They found that wildtype PSM cells could rapidly correct for phase fluctuations in Hes7 oscillations, whereas loss of the Notch modulator Lfng (602576) led to loss of synchrony between PSM cells. Moreover, Hes7 oscillations were severely dampened in individual cells of Lfng-null PSM. When Lfng-null PSM cells were completely dissociated, the amplitude and periodicity of Hes7 oscillations were almost normal, suggesting that Lfng is involved mostly in cell-cell coupling. Mixed cultures of wildtype and Lfng-null PSM cells, and an optogenetic Notch signaling reporter assay, revealed that Lfng delayed the signal-sending process of intercellular Notch signaling transmission. These results, as well as mathematical modeling, suggested that Lfng-null PSM cells shortened the coupling delay, thereby approaching oscillation or amplitude death of coupled oscillators. A small compound that lengthened the coupling delay partially rescued the amplitude and synchrony of Hes7 oscillations in Lfng-null PSM cells. The findings revealed a delay control mechanism of the oscillatory networks involved in somite segmentation and showed that intercellular coupling with the correct delay is essential for synchronized oscillation.
Matsuda et al. (2020) used human induced pluripotent stem cells for in vitro induction of PSM and its derivatives to model human somitogenesis, with a focus on the human segmentation clock. The authors observed oscillatory expression of core segmentation clock genes, including HES7 and DKK1 (605189), determined the period of the human segmentation clock to be around 5 hours, and demonstrated the presence of dynamic traveling wave-like gene expression in in vitro-induced human PSM. Identification and comparison of oscillatory genes in human and mouse PSM derived from pluripotent stem cells revealed species-specific and shared molecular components and pathways associated with the putative mouse and human segmentation clocks. Knockout of genes mutated in patients with segmentation defects of vertebrae, including HES7, LFNG, DLL3 (602768), and MESP2 (605195), followed by analysis of patient-like and patient-derived induced pluripotent stem cells revealed gene-specific alterations in oscillation, synchronization, or differentiation properties.
To investigate interspecies differences in the time scale of development, Matsuda et al. (2020) recapitulated murine and human segmentation clocks displaying 2- to 3-hour and 5- to 6-hour oscillation periods, respectively. Interspecies genome-swapping analyses showed that the period difference was not due to sequence differences in HES7. Instead, multiple biochemical reactions of HES7, including degradation and expression delays, were slower in human cells than in mouse cells. With the measured biochemical parameters, the authors built a mathematical model accounting for the 2- to 3-fold period difference between the species.
In the proband of a consanguineous family of Caucasian Mediterranean origin with spondylocostal dysostosis mapping to chromosome 17p13 (SCDO4; 613686), Sparrow et al. (2008) identified homozygosity for a missense mutation in the HES7 gene (R25W; 608059.0001).
In a brother and sister with SCDO from a nonconsanguineous Italian family, Sparrow et al. (2010) sequenced the 4 genes known to cause SCDO and identified compound heterozygosity for missense mutations in the HES7 gene (608059.0002 and 608059.0003).
In 7 patients from 3 families with SCDO, Sparrow et al. (2013) identified a homozygous frameshift mutation in the HES7 gene (608059.0004) that resulted in significant reduction of HES7 protein function. Four patients were from a consanguineous Arab family and the other patients were from 2 additional families from the same geographic area. Three patients also had dextrocardia with situs inversus and 2 patients also had neural tube defects.
Cats with variably shortened and/or kinked tails are widespread in Southeast Asia and southern China. Xu et al. (2016) established a 2-generation pedigree of 13 cats in which the dam appeared to be heterozygous for a tail with medium kink and the sire was wildtype. Radiography revealed that wildtype cats had 22 caudal vertebrae with no sign of deformity, whereas the kinked-tail dam and affected offspring exhibited reduced number of vertebrae and variable deformity, including hemivertebrae and block caudal vertebrae. Linkage analysis and whole-genome sequencing revealed that tail shortening and kinking was due to a c.5T-C transition in Hes7, resulting in a val2-to-ala (V2A) substitution. Val2 lies upstream of the bHLH domain and is completely conserved in vertebrates. In an extended sampling of 245 unrelated cats, the authors found that a significant number with shortened and/or kinked tails carried the Hes7 mutation. The results suggested that V2A is strongly associated with short/kinked tail with a dominant mode of inheritance. Cats homozygous for the V2A mutation showed tails with extreme kink, whereas heterozygotes had either minor or medium kink, suggesting a dose effect of V2A on tail morphology. No wildtype cats carried the mutation. Other than the tail abnormality, feral cats heterozygous or homozygous for V2A appeared normal and had no apparent health hazards.
In the proband of a consanguineous family of Caucasian Mediterranean origin with spondylocostal dysostosis (SCDO4; 613686), Sparrow et al. (2008) identified homozygosity for a 73C-T transition in exon 2 of the HES7 gene, resulting in an arg25-to-trp (R25W) substitution at an evolutionarily conserved residue in the DNA-binding domain. The mutation was found in heterozygosity in the parents and 1 unaffected sib, but was not detected in 110 racially matched controls. Expression studies in mouse muscle satellite C2C12 cells using the R25W mutant in an N-box assay showed that levels of transcription were significantly increased above the control, suggesting that the R25W mutant lacks normal repression activity. In an E-box (see 147141) assay, mutant HES7 did not repress the reporter significantly over the control, suggesting that R25W also impairs the ability of HES7 to heterodimerize with E47.
In a sister and brother with spondylocostal dysostosis (SCDO4; 613686), Sparrow et al. (2010) identified compound heterozygosity for a 172A-G transition in exon 3 of the HES7 gene, resulting in an ile58-to-val (I58V; 608059.0003) substitution, and a 556G-T transversion in exon 4, resulting in an asp186-to-tyr (D186Y) substitution. The unaffected parents were each heterozygous for 1 of the mutations, and 1 unaffected sib carried the D186Y allele; neither mutation was found in 110 ethnically matched controls. In vitro functional analysis demonstrated that the D186Y mutant was unable to repress gene expression by DNA binding or protein heterodimerization.
For discussion of the ile58-to-val (I58V) mutation in the HES7 gene that was found in compound heterozygous state in sibs with spondylocostal dysostosis-4 (SCDO4; 613686) by Sparrow et al. (2010), see 608059.0002.
In 4 patients from a large consanguineous Arab family with spondylocostal dysostosis (SCDO4; 613686), Sparrow et al. (2013) identified a homozygous 10-bp duplication (c.400_409dupAAACCGCCCC) in exon 4 of the HES7 gene, predicting a frameshift and premature termination (Arg137GlnfsTer42). The same mutation was identified in 3 patients in 2 additional families from the same geographic area. Three patients also has dextrocardia with situs inversus and 2 patients also had neural tube defects. Functional analysis showed that the mutation resulted in a significant reduction in the repressive activity of HES7.
Bessho, Y., Miyoshi, G., Sakata, R., Kageyama, R. Hes7: a bHLH-type repressor gene regulated by Notch and expressed in the presomitic mesoderm. Genes Cells 6: 175-185, 2001. [PubMed: 11260262] [Full Text: https://doi.org/10.1046/j.1365-2443.2001.00409.x]
Diaz-Cuadros, M., Wagner, D. E., Budjan, C., Hubaud, A., Tarazona, O. A., Donelly, S., Michaut, A., Al Tanoury, Z., Yoshioka-Kobayashi, K., Niino, Y., Kageyama, R., Miyawaki, A., Touboul, J., Pourguie, O. In vitro characterization of the human segmentation clock. Nature 580: 113-118, 2020. [PubMed: 31915384] [Full Text: https://doi.org/10.1038/s41586-019-1885-9]
Gross, M. B. Personal Communication. Baltimore, Md. 12/18/2013.
Hirata, H., Bessho, Y., Kokubu, H., Masamizu, Y., Yamada, S., Lewis, J., Kageyama, R. Instability of Hes7 protein is crucial for the somite segmentation clock. Nature Genet. 36: 750-754, 2004. [PubMed: 15170214] [Full Text: https://doi.org/10.1038/ng1372]
Matsuda, M., Hayashi, H., Garcia-Ojalvo, J., Yoshioka-Kobayashi, K., Kageyama, R., Yamanaka, Y., Ikeya, M., Toguchida, J., Alev, C., Ebisuya, M. Species-specific segmentation clock periods are due to differential biochemical reaction speeds. Science 369: 1450-1455, 2020. [PubMed: 32943519] [Full Text: https://doi.org/10.1126/science.aba7668]
Matsuda, M., Yamanaka, Y., Uemura, M., Osawa, M., Saito, M. K., Nagahashi, A., Nishio, M., Guo, L., Ikegawa, S., Sakurai, S., Kihara, S., Maurissen, T. L., and 10 others. Recapitulating the human segmentation clock with pluripotent stem cells. Nature 580: 124-129, 2020. [PubMed: 32238941] [Full Text: https://doi.org/10.1038/s41586-020-2144-9]
Sparrow, D. B., Faqeih, E. A., Sallout, B., Alswaid, A., Ababneh, F., Al-Sayed, M., Rukban, H., Eyaid, W. M., Kageyama, R., Ellard, S., Turnpenny, P. D., Dunwoodie, S. L. Mutation of HES7 in a large extended family with spondylocostal dysostosis and dextrocardia with situs inversus. Am. J. Med. Genet. 161A: 2244-2249, 2013. [PubMed: 23897666] [Full Text: https://doi.org/10.1002/ajmg.a.36073]
Sparrow, D. B., Guillen-Navarro, E., Fatkin, D., Dunwoodie, S. L. Mutation of hairy-and-enhancer-of-split-7 in humans causes spondylocostal dysostosis. Hum. Molec. Genet. 17: 3761-3766, 2008. [PubMed: 18775957] [Full Text: https://doi.org/10.1093/hmg/ddn272]
Sparrow, D. B., Sillence, D., Wouters, M. A., Turnpenny, P. D., Dunwoodie, S. L. Two novel missense mutations in hairy-and-enhancer-of-split-7 in a family with spondylocostal dysostosis. Europ. J. Hum. Genet. 18: 674-679, 2010. [PubMed: 20087400] [Full Text: https://doi.org/10.1038/ejhg.2009.241]
Xu, X., Sun, X., Hu, X.-S., Zhuang, Y., Liu, Y.-C., Meng, H., Miao, L., Yu, H., Luo, S.-J. Whole genome sequencing identifies a missense mutation in HES7 associated with short tails in Asian domestic cats. Sci. Rep. 6: 31583, 2016. Note: Electronic Article. [PubMed: 27560986] [Full Text: https://doi.org/10.1038/srep31583]
Yoshioka-Kobayashi, K., Matsumiya, M., Niino, Y., Isomura, A., Kori, H., Miyawaki, A., Kageyama, R. Coupling delay controls synchronized oscillation in the segmentation clock. Nature 580: 119-123, 2020. [PubMed: 31915376] [Full Text: https://doi.org/10.1038/s41586-019-1882-z]