HES7 gene

(HES7) or bHLHb37 is protein coding mammalian gene found on chromosome 17 in humans. HES7 is a member of the Hairy and Enhancer of Split families of Basic helix-loop-helix proteins. The gene product is a transcription factor and is expressed cyclically in the presomitic mesoderm as part of the Notch signalling pathway.[5] HES7 is involved in the segmentation of somites from the presomitic mesoderm in vertebrates. The HES7 gene is self-regulated by a negative feedback loop in which the gene product can bind to its own promoter. This causes the gene to be expressed in an oscillatory manner. The HES7 protein also represses expression of Lunatic Fringe (LFNG)[6] thereby both directly and indirectly regulating the Notch signalling pathway. Mutations in HES7 can result in deformities of the spine, ribs and heart. Spondylocostal dysostosis is a common disease caused by mutations in the HES7 gene. The inheritance pattern of Spondylocostal dysostosis is autosomal recessive.[7]

HES7
Identifiers
AliasesHES7, SCDO4, bHLHb37, hes family bHLH transcription factor 7, HES7 gene
External IDsOMIM: 608059 MGI: 2135679 HomoloGene: 23779 GeneCards: HES7
Gene location (Human)
Chr.Chromosome 17 (human)[1]
Band17p13.1Start8,120,592 bp[1]
End8,124,106 bp[1]
Orthologs
SpeciesHumanMouse
Entrez

84667

84653

Ensembl

ENSG00000179111

ENSMUSG00000023781

UniProt

Q9BYE0

Q8BKT2

RefSeq (mRNA)

NM_001165967
NM_032580

NM_033041

RefSeq (protein)

NP_001159439
NP_115969

NP_149030

Location (UCSC)Chr 17: 8.12 – 8.12 MbChr 11: 69.12 – 69.12 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Gene

The HES7 transcription factor belongs to the Hairy and Enhancer of split families of bHLH transcription factors.[8] The gene that encodes the human HES7 protein is 5kb long and is found on chromosome 17, on the short arm at position 13.1.[9] from base pair 8,120,590 to 8,126,032. In mice, HES7 is located on chromosome 11.[10] HES7 has 62 known orthologues.[11] The HES7 gene is expressed in the presomitic mesoderm [10] where expression fluctuates in two hour cycles.[12] HES7 is regulated by the Notch signalling pathway that functions in vertebrates and invertebrates by mediating cell fate and differentiation.[13]

The HES7 gene product functions to repress expression of genes with promoters containing an N-box or E-box. HES7 also has been shown to negatively regulate expression of genes activated by the E47 transcription factor.[10] HES7 regulates its own expression through a negative feedback loop by binding to its own promoter. This feedback mechanism allows the HES7 protein to accumulate and be degraded so that its expression oscillates in a two-hour cycle. HES7 also negatively regulates Lunatic Fringe protein (Lfng).[14] Lfng encodes an acetylglucosaminyl transferase that regulates expression in the Notch signalling pathway.[6] By self-regulating and regulating the Lfng protein, HES7 both directly and indirectly alters expression in the Notch signalling pathway.

Mutations

Several mutations in HES7 have been associated with disease.

Common mutations in humans

Mutations to HES7 can lead to abnormalities in formation of heart, vertebral and neural tube. Homozygous mutations in HES7 have been associated with spondylocostal dystostosis and dextrocardia. Dextrocardia may be accompanied by situs invertus.[15] A single nucleotide mutation in the 3'UTR has been associated with Coats Plus Syndrome in addition to Dextrocardia.[16]

Animal models

Studies of animal embryos have linked mutations in HES7 to congenital scoliosis.[17] In canines, exonic deletions in HES7 have been shown to mirror human disease and cause spondylocostal dystostosis in miniature Schnauzer dogs.[18] Missense mutations in HES7 have been linked to short and kinked tails in Asian Domestic Cats.[19] Homozygotes for a V2A missense mutation in a conserved vertebrate sequence of HES7 resulted in kinked tails while heterozygotes for the mutation presented with moderately kinked tails.[20]

Protein

Studies with mouse HES7 have demonstrated that the gene contains 4 exons.[10] There are three known human HES7 variants due to alterative splicing.[21] The gene product is a transcription factor protein. The Helix-loop-helix domain is located at the N-terminal end of the protein. Both the human and the mouse protein have been shown to contain 225 amino acids and feature an orange domain as well as a conserved sequence of four amino acids at the C-terminal end. The four amino acids are Tryptophan-Arginine-Proline-Tryptophan.[10] This conserved sequence of four amino acids binds Groucho/TLE family members.[22] Groucho/TLE are transcriptional corepressors. Hairy-related proteins can direct these transcriptional corepressors to target genes.[23] Orange domains are motifs of ~35 amino acids that are found on the C-terminal side of basic helix-loop-helix domains in some transcription factors in eukaryotic organisms. Proteins with Orange domains are divided into four subfamilies, three in which all proteins contain a basic helix-loop-helix domain. The subfamilies that contain Orange domains and basic helix-loop-helix domains are Hairy, Enhancer of Split, and Hey. Transcription factors with Orange domains bind DNA and regulate biological processes such as cell differentiation and embryonic patterning.[22]

Function

The HES7 protein is a transcription factor that functions as a transcriptional repressor. It is involved in somitogenesis, an important cycle in vertebrate development. Somitogenesis involves the early segmentation of vertebrates.[5] HES7 is involved in segmenting the presomitic mesoderm into somites.[12] Oscillating expression of HES7 in the presomitic mesoderm occurs in a two-hour cycle and is regulated by a negative feedback loop.[24] This cycle of accumulation and degradation of the HES7 protein has been proposed as the basis for the somite segmentation clock.[25] The cyclic nature of HES7 relies on proteasome-mediated degradation.[14] Each cycle of HES7 expression coincides with the formation of a pair of somites. The half life of the HES7 protein is thought to be essential for proper function of the HES7 gene. The importance of accuracy in the two hour expression cycle was highlighted in an experiment where mice expressing HES7 with a mutation that allowed for a longer half life while retaining normal repressor function presented with abnormal segmentation.[25] The 3'UTR was demonstrated as necessary for sufficient accumulation of HES7 protein to function. This was determined when transcripts with an improperly spliced intron in the 3'UTR were degraded prematurely.[26] The correct number of introns has also been demonstrated as necessary to maintain the cyclic rhythm. Shortening the delay in accumulation of the HES7 protein by reducing the number of introns resulted in an increased number of somites.[24]

Nonfunctional HES7 protein results in errors in segmentation of the presomitic mesoderm. Mutations can result in malformed spine, ribs, heart and neural tube.[15] The following conditions can result from errors in segmentation due to mutations in HES7:

  • Spondylocostal dysostosis is characterized by abnormalities of the spine and ribs. Vertebrae may be fused together or abnormally shaped. Rib bones also may be fused together or missing entirely. These abnormalities can result in scoliosis. These symptoms lead to dwarfism where an individual has a shortened body length with legs and arms of regular length. The inheritance pattern of Spondylocostal dysostosis is autosomal recessive.[7]
  • Dextrocardia is characterized by the heart pointing to the right side of the chest, when it normally points to the left. Dextrocardia may or may not be accompanied by situs inversus.[27]
  • Dextrocardia with Situs inversus results when, in addition to the heart, the major visceral organs of the body form in the mirror image of their normal positioning.[28]
  • Scoliosis is characterized by a curvature of the spine. The curve may be C-shaped or S-shaped.[29]
  • Spina bifida is a neural tube defect. It is characterized by a malformed spine when the neural tube does not properly close correctly. Spina bifida may cause physical and intellectual disability.[30] Types of spina bifida that have been documented in individuals homozygous for mutations in HES7 are Spina bifida occulta and Myelomeningocele.[15]
  • Chiari malformation results from neural tube defects and affects the base of the skull and the cerebellum. With Chiari malformation, the cerebellum extends lower than the base of the skull into the upper spinal canal.[31]

References
  1. GRCh38: Ensembl release 89: ENSG00000179111 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000023781 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Maroto M, Bone RA, Dale JK (July 2012). "Somitogenesis". Development. 139 (14): 2453–2456. doi:10.1242/dev.069310. PMC 3928720. PMID 22736241.
  6. Dunwoodie SL (February 2009). "Mutation of the fucose-specific beta1,3 N-acetylglucosaminyltransferase LFNG results in abnormal formation of the spine" (PDF). Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1792 (2): 100–11. doi:10.1016/j.bbadis.2008.11.003. PMID 19061953.
  7. Reference, Genetics Home. "spondylocostal dysostosis". Genetics Home Reference. Retrieved 2017-11-30.
  8. "HES7 hes family bHLH transcription factor 7 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2017-12-01.
  9. "HES7 hes family bHLH transcription factor 7 [ Homo sapiens (human) ]". NCBI. September 3, 2017.
  10. Bessho Y, Miyoshi G, Sakata R, Kageyama R (February 2001). "Hes7: a bHLH-type repressor gene regulated by Notch and expressed in the presomitic mesoderm". Genes to Cells. 6 (2): 175–85. doi:10.1046/j.1365-2443.2001.00409.x. PMID 11260262.
  11. "Gene: HES7 (ENSG00000179111) - Orthologues - Homo sapiens - Ensembl genome browser 90". www.ensembl.org-gb. Retrieved 2017-11-30.
  12. Bessho Y, Sakata R, Komatsu S, Shiota K, Yamada S, Kageyama R (October 2001). "Dynamic expression and essential functions of Hes7 in somite segmentation". Genes & Development. 15 (20): 2642–7. doi:10.1101/gad.930601. PMC 312810. PMID 11641270.
  13. Baron M (April 2003). "An overview of the Notch signalling pathway". Seminars in Cell & Developmental Biology. 14 (2): 113–9. doi:10.1016/s1084-9521(02)00179-9. PMID 12651094.
  14. Bessho Y, Hirata H, Masamizu Y, Kageyama R (June 2003). "Periodic repression by the bHLH factor Hes7 is an essential mechanism for the somite segmentation clock". Genes & Development. 17 (12): 1451–6. doi:10.1101/gad.1092303. PMC 196074. PMID 12783854.
  15. Sparrow DB, Faqeih EA, Sallout B, Alswaid A, Ababneh F, Al-Sayed M, Rukban H, Eyaid WM, Kageyama R, Ellard S, Turnpenny PD, Dunwoodie SL (September 2013). "Mutation of HES7 in a large extended family with spondylocostal dysostosis and dextrocardia with situs inversus". American Journal of Medical Genetics. Part A. 161A (9): 2244–9. doi:10.1002/ajmg.a.36073. PMID 23897666. S2CID 24275928.
  16. Netravathi M, Kumari R, Kapoor S, Dakle P, Dwivedi MK, Roy SD, Pandey P, Saini J, Ramakrishna A, Navalli D, Satishchandra P, Pal PK, Kumar A, Faruq M (February 2015). "Whole exome sequencing in an Indian family links Coats plus syndrome and dextrocardia with a homozygous novel CTC1 and a rare HES7 variation". BMC Medical Genetics. 16: 5. doi:10.1186/s12881-015-0151-8. PMC 4422476. PMID 25928698.
  17. Qiu XS, Zhou S, Jiang H, Ji ML, Ding Q, Lv F, Liu Z, Tang N, Cheng JC, Qiu Y (2012). "Mutation analysis of MESP2, HES7 and DUSP6 gene exons in patients with congenital scoliosis". Studies in Health Technology and Informatics. 176: 52–5. PMID 22744456.
  18. Willet CE, Makara M, Reppas G, Tsoukalas G, Malik R, Haase B, Wade CM (2015). "Canine disorder mirrors human disease: exonic deletion in HES7 causes autosomal recessive spondylocostal dysostosis in miniature Schnauzer dogs". PLOS ONE. 10 (2): e0117055. Bibcode:2015PLoSO..1017055W. doi:10.1371/journal.pone.0117055. PMC 4319916. PMID 25659135.
  19. Xu X, Sun X, Hu XS, Zhuang Y, Liu YC, Meng H, Miao L, Yu H, Luo SJ (August 2016). "Whole Genome Sequencing Identifies a Missense Mutation in HES7 Associated with Short Tails in Asian Domestic Cats". Scientific Reports. 6 (1): 31583. Bibcode:2016NatSR...631583X. doi:10.1038/srep31583. PMC 4997960. PMID 27560986.
  20. Xu X, Sun X, Hu XS, Zhuang Y, Liu YC, Meng H, Miao L, Yu H, Luo SJ (August 2016). "Whole Genome Sequencing Identifies a Missense Mutation in HES7 Associated with Short Tails in Asian Domestic Cats". Scientific Reports. 6: 31583. Bibcode:2016NatSR...631583X. doi:10.1038/srep31583. PMC 4997960. PMID 27560986.
  21. "Gene: HES7 (ENSG00000179111) - Summary - Homo sapiens - Ensembl genome browser 90". www.ensembl.org-gb. Retrieved 2017-11-30.
  22. EMBL-EBI, InterPro. "Orange domain (IPR003650) < InterPro < EMBL-EBI". www.ebi.ac.uk. Retrieved 2017-11-30.
  23. "HES7 - Transcription factor HES-7 - Homo sapiens (Human) - HES7 gene & protein". www.uniprot.org. Retrieved 2017-12-01.
  24. Harima Y, Takashima Y, Ueda Y, Ohtsuka T, Kageyama R (January 2013). "Accelerating the tempo of the segmentation clock by reducing the number of introns in the Hes7 gene". Cell Reports. 3 (1): 1–7. doi:10.1016/j.celrep.2012.11.012. PMID 23219549.
  25. Hirata H, Bessho Y, Kokubu H, Masamizu Y, Yamada S, Lewis J, Kageyama R (July 2004). "Instability of Hes7 protein is crucial for the somite segmentation clock". Nature Genetics. 36 (7): 750–4. doi:10.1038/ng1372. PMID 15170214.
  26. Fujimuro T, Matsui T, Nitanda Y, Matta T, Sakumura Y, Saito M, Kohno K, Nakahata Y, Bessho Y (September 2014). "Hes7 3'UTR is required for somite segmentation function". Scientific Reports. 4 (1): 6462. Bibcode:2014NatSR...4E6462F. doi:10.1038/srep06462. PMC 4173035. PMID 25248974.
  27. "Dextrocardia : MedlinePlus Medical Encyclopedia". medlineplus.gov. Retrieved 2017-11-30.
  28. "Dextrocardia with situs inversus | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Retrieved 2017-11-30.
  29. Director, Nancy Garrick, Deputy (2017-04-07). "NIAMS Health Information on Scoliosis". National Institute of Arthritis and Musculoskeletal and Skin Diseases. Retrieved 2017-12-01.
  30. "Facts | Spina Bifida | NCBDDD | CDC". Centers for Disease Control and Prevention. 2017-11-20. Retrieved 2017-12-01.
  31. "Chiari Malformation Fact Sheet | National Institute of Neurological Disorders and Stroke". www.ninds.nih.gov. Retrieved 2017-12-01.
This article is issued from Wikipedia. The text is licensed under Creative Commons - Attribution - Sharealike. Additional terms may apply for the media files.