{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T06:12:25Z","timestamp":1791353545746,"version":"4.3.1"},"reference-count":44,"publisher":"The Company of Biologists","issue":"24","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2001,12,15]]},"abstract":"<jats:p>The homeobox gene Hesx1\/HESX1 has been implicated in the establishment of anterior pattern in the central nervous system (CNS) in a number of vertebrate species. Its role in pituitary development has been documented through loss-of-function studies in the mouse. A homozygous missense point mutation resulting in a single amino acid substitution, Arg160Cys (R160C), is associated with a heritable form of the human condition of septo-optic dysplasia (SOD). We have examined the phenotype of affected members in this pedigree in more detail and demonstrate for the first time a genetic basis for midline defects associated with an undescended or ectopic posterior pituitary. A similar structural pituitary abnormality was observed in a second patient heterozygous for another mutation in HESX1, Ser170Leu (S170L). Association of S170L with a pituitary phenotype may be a direct consequence of the HESX1 mutation since S170L is also associated with a dominant familial form of pituitary disease. However, a third mutation in HESX1, Asn125Ser (N125S), occurs at a high frequency in the Afro-Caribbean population and may therefore reflect a population-specific polymorphism. To investigate the molecular basis for these clinical phenotypes, we have examined the impact of these mutations on the regulatory functions of HESX1. We show that Hesx1 is a promoter-specific transcriptional repressor with a minimal 36 amino acid repression domain which can mediate promoter-specific repression by suppressing the activity of homeodomain-containing activator proteins. Mutations in HESX1 associated with pituitary disease appear to modulate the DNA-binding affinity of HESX1 rather than its transcriptional activity. Wild-type HESX1 binds a dimeric homeodomain site with high affinity (Kd 31 nM) whilst HESX1(S170L) binds with a 5-fold lower activity (Kd 150 nM) and HESX1(R160C) does not bind at all. Although HESX1(R160C) has only been shown to be associated with the SOD phenotype in children homozygous for the mutation, HESX1(R160C) can inhibit DNA binding by wild-type HESX1 both in vitro and in vivo in cell culture. This dominant negative activity of HESX1(R160C) is mediated by the Hesx1 repression domain, supporting the idea that the repression domain is implicated in interactions between homeodomain proteins. Our data suggest a possible molecular paradigm for the dominant inheritance observed in some pituitary disorders.<\/jats:p>","DOI":"10.1242\/dev.128.24.5189","type":"journal-article","created":{"date-parts":[[2021,4,26]],"date-time":"2021-04-26T00:45:25Z","timestamp":1619397925000},"page":"5189-5199","source":"Crossref","is-referenced-by-count":109,"title":["Molecular effects of novel mutations in\n                    <i>Hesx1\/HESX1<\/i>\n                    associated with human pituitary disorders"],"prefix":"10.1242","volume":"128","author":[{"given":"Joshua M.","family":"Brickman","sequence":"first","affiliation":[{"name":"Division of Mammalian Development,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie","family":"Clements","sequence":"additional","affiliation":[{"name":"Division of Mammalian Development,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Tyrell","sequence":"additional","affiliation":[{"name":"Division of Protein Structure, National Institute for Medical Research, The Ridgeway, London NW7 1AA, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"McNay","sequence":"additional","affiliation":[{"name":"Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathryn","family":"Woods","sequence":"additional","affiliation":[{"name":"Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin","family":"Warner","sequence":"additional","affiliation":[{"name":"Department of Paediatric Endocrinology, John Radcliffe Hospital, Headley Way, Headington, Oxford OX3 9DU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Stewart","sequence":"additional","affiliation":[{"name":"Division of Mammalian Development,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosa S. P.","family":"Beddington","sequence":"additional","affiliation":[{"name":"Division of Mammalian Development,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mehul","family":"Dattani","sequence":"additional","affiliation":[{"name":"Division of Mammalian Development,"},{"name":"Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK"},{"name":"Present address: Centre for Genome Research, The University of Edinburgh, Kings Buildings, West Mains Road, Edinburgh EH9 3JQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","reference":[{"key":"2021042604130223800_ARSLANIAN-ETAL-1984","doi-asserted-by":"crossref","unstructured":"Arslanian, S. A., Rothfus, W. E., Foley, T. P., Jr and Becker, D. J. (1984). Hormonal, metabolic, and neuroradiologic abnormalities associated with septo-optic dysplasia. Acta Endocrinol.107, 282-288.","DOI":"10.1530\/acta.0.1070282"},{"key":"2021042604130223800_BRICKMAN-ETAL-1999","doi-asserted-by":"crossref","unstructured":"Brickman, J. M., Adam, M. and Ptashne, M. (1999). Interactions between an HMG-1 protein and members of the rel family. Proc. Natl. Acad. Sci. USA96, 10679-10683.","DOI":"10.1073\/pnas.96.19.10679"},{"key":"2021042604130223800_BRICKMAN-ETAL-2000","doi-asserted-by":"crossref","unstructured":"Brickman, J. M., Jones, C. M., Clements, M., Smith, J. C. and Beddington, R. S. P. (2000). Hex is a transcriptional repressor that contributes to anterior identity and suppresses Spemann organiser function. Development127, 2303-2315.","DOI":"10.1242\/dev.127.11.2303"},{"key":"2021042604130223800_DATTANI-ETAL-1998","doi-asserted-by":"crossref","unstructured":"Dattani, M. T., Martinez-Barbera, J. P., Thomas, P. Q., Brickman, J. M., Gupta, R., Martensson, I. L., Toresson, H., Fox, M., Wales, J. K., Hindmarsh, P. C. et al. (1998). Mutations in the homeobox gene HESX1\/Hesx1 associated with septo-optic dysplasia in human and mouse. Nat. Genet.19, 125-133.","DOI":"10.1038\/477"},{"key":"2021042604130223800_DATTANI-ETAL-1999","doi-asserted-by":"crossref","unstructured":"Dattani, M. T., Martinez-Barbera, J. P., Thomas, P. Q., Brickman, J. M., Gupta, R., Wales, J. K., Hindmarsh, P. C., Beddington, R. S. and Robinson, I. C. (1999). HESX1: a novel gene implicated in a familial form of septo-optic dysplasia. Acta Paediatr.Suppl. 88, 49-54.","DOI":"10.1111\/j.1651-2227.1999.tb14403.x"},{"key":"2021042604130223800_DESPLAN-ETAL-1988","doi-asserted-by":"crossref","unstructured":"Desplan, C., Theis, J. and O\u2019Farrell, P. H. (1988). The sequence specificity of homeodomain-DNA interaction. Cell54, 1081-1090.","DOI":"10.1016\/0092-8674(88)90123-7"},{"key":"2021042604130223800_DUBNICOFF-ETAL-1997","doi-asserted-by":"crossref","unstructured":"Dubnicoff, T., Valentine, S. A., Chen, G., Shi, T., Lengyel, J. A., Paroush, Z. and Courey, A. J. (1997). Conversion of dorsal from an activator to a repressor by the global corepressor Groucho. Genes Dev.11, 2952-2957.","DOI":"10.1101\/gad.11.22.2952"},{"key":"2021042604130223800_DUBOULE-1994","doi-asserted-by":"crossref","unstructured":"Duboule, D. (1994). Guidebook to the Homeobox Genes. Oxford, New York: Oxford University Press.","DOI":"10.1093\/oso\/9780198599395.001.0001"},{"key":"2021042604130223800_EMAMI-AND-CAREY-1992","doi-asserted-by":"crossref","unstructured":"Emami, K. H. and Carey, M. (1992). A synergistic increase in potency of a multimerized VP16 transcriptional activation domain. EMBO J.11, 5005-5012.","DOI":"10.1002\/j.1460-2075.1992.tb05607.x"},{"key":"2021042604130223800_FISHER-ETAL-1989","doi-asserted-by":"crossref","unstructured":"Fisher, J. P., Hope, S. A. and Hooper, M. L. (1989). Factors influencing the differentiation of embryonal carcinoma and embryo-derived stem cells. Exp. Cell Res.182, 403-414.","DOI":"10.1016\/0014-4827(89)90245-0"},{"key":"2021042604130223800_FOFANOVA-ETAL-2000","doi-asserted-by":"crossref","unstructured":"Fofanova, O., Takamura, N., Kinoshita, E., Vorontsov, A., Vladimirova, V., Dedov, I., Peterkova, V. and Yamashita, S. (2000). MR imaging of the pituitary gland in children and young adults with congenital combined pituitary hormone deficiency associated with PROP1 mutations. Am. J. Roentgenol.174, 555-559.","DOI":"10.2214\/ajr.174.2.1740555"},{"key":"2021042604130223800_GEHRING-ETAL-1994","doi-asserted-by":"crossref","unstructured":"Gehring, W. J., Affolter, M. and Burglin, T. (1994). Homeodomain proteins. Annu. Rev. Biochem.63, 487-526.","DOI":"10.1146\/annurev.bi.63.070194.002415"},{"key":"2021042604130223800_GERMAIN-ETAL-2000","doi-asserted-by":"crossref","unstructured":"Germain, S., Howell, M., Esslemont, G. M. and Hill, C. S. (2000). Homeodomain and winged-helix transcription factors recruit activated Smads to distinct promoter elements via a common Smad interaction motif. Genes Dev.14, 435-451.","DOI":"10.1101\/gad.14.4.435"},{"key":"2021042604130223800_HANNA-ROSE-AND-HANSEN-1996","doi-asserted-by":"crossref","unstructured":"Hanna-Rose, W. and Hansen, U. (1996). Active repression mechanisms of eukaryotic transcription repressors. Trends Genet. 12, 229-234.","DOI":"10.1016\/0168-9525(96)10022-6"},{"key":"2021042604130223800_HENRY-AND-MELTON-1998","doi-asserted-by":"crossref","unstructured":"Henry, G. L. and Melton, D. A. (1998). Mixer, a homeobox gene required for endoderm development. Science281, 91-96.","DOI":"10.1126\/science.281.5373.91"},{"key":"2021042604130223800_HERMESZ-ETAL-1996","doi-asserted-by":"crossref","unstructured":"Hermesz, E., Mackem, S. and Mahon, K. A. (1996). Rpx: a novel anterior-restricted homeobox gene progressively activated in the prechordal plate, anterior neural plate and Rathke\u2019s pouch of the mouse embryo. Development122, 41-52.","DOI":"10.1242\/dev.122.1.41"},{"key":"2021042604130223800_JIMENEZ-ETAL-1997","doi-asserted-by":"crossref","unstructured":"Jimenez, G., Paroush, Z. and Ish-Horowicz, D. (1997). Groucho acts as a corepressor for a subset of negative regulators, including Hairy and Engrailed. Genes Dev.11, 3072-3082.","DOI":"10.1101\/gad.11.22.3072"},{"key":"2021042604130223800_JIMENEZ-ETAL-1999","doi-asserted-by":"crossref","unstructured":"Jimenez, G., Verrijzer, C. P. and Ish-Horowicz, D. (1999). A conserved motif in goosecoid mediates groucho-dependent repression in Drosophila embryos. Mol. Cell Biol.19, 2080-2087.","DOI":"10.1128\/MCB.19.3.2080"},{"key":"2021042604130223800_LATINKIC-AND-SMITH-1999","unstructured":"Latinkic, B. V. and Smith, J. C. (1999). Goosecoid and mix.1 repress Brachyury expression and are required for head formation in Xenopus. Development126, 1769-1779."},{"key":"2021042604130223800_LEVINE-AND-MANLEY-1989","doi-asserted-by":"crossref","unstructured":"Levine, M. and Manley, J. L. (1989). Transcriptional repression of eukaryotic promoters. Cell59, 405-408.","DOI":"10.1016\/0092-8674(89)90024-X"},{"key":"2021042604130223800_LIN-ETAL-1988","doi-asserted-by":"crossref","unstructured":"Lin, Y. S., Carey, M. F., Ptashne, M. and Green, M. R. (1988). GAL4 derivatives function alone and synergistically with mammalian activators in vitro. Cell54, 659-664.","DOI":"10.1016\/S0092-8674(88)80010-2"},{"key":"2021042604130223800_LU-AND-KAMPS-1996","doi-asserted-by":"crossref","unstructured":"Lu, Q. and Kamps, M. P. (1996). Structural determinants within Pbx1 that mediate cooperative DNA binding with pentapeptide containing Hox proteins: proposal for a model of a Pbx1-Hox-DNA complex. Mol. Cell Biol.16, 1632-1640.","DOI":"10.1128\/MCB.16.4.1632"},{"key":"2021042604130223800_MAILHOS-ETAL-1998","doi-asserted-by":"crossref","unstructured":"Mailhos, C., Andre, S., Mollereau, B., Goriely, A., Hemmati-Brivanlou, A. and Desplan, C. (1998). Drosophila Goosecoid requires a conserved heptapeptide for repression of paired-class homeoprotein activators. Development125, 937-947.","DOI":"10.1242\/dev.125.5.937"},{"key":"2021042604130223800_MCKNIGHT-AND-TJIAN-1986","doi-asserted-by":"crossref","unstructured":"McKnight, S. and Tjian, R. (1986). Transcriptional selectivity of viral genes in mammalian cells. Cell46, 795-805.","DOI":"10.1016\/0092-8674(86)90061-9"},{"key":"2021042604130223800_MEAD-ETAL-1996","doi-asserted-by":"crossref","unstructured":"Mead, P. E., Brivanlou, I. H., Kelley, C. M. and Zon, L. I. (1996). BMP-4-responsive regulation of dorsal-ventral patterning by the homeobox protein Mix.1. Nature382, 357-360.","DOI":"10.1038\/382357a0"},{"key":"2021042604130223800_MOUNTFORD-ETAL-1994","doi-asserted-by":"crossref","unstructured":"Mountford, P., Zevnik, B., Duwel, A., Nichols, J., Li, M., Dani, C., Robertson, M., Chambers, I. and Smith, A. (1994). Dicistronic targeting constructs: reporters and modifiers of mammalian gene expression. Proc. Natl. Acad. Sci. USA91, 4303-4307.","DOI":"10.1073\/pnas.91.10.4303"},{"key":"2021042604130223800_NETCHINE-ETAL-2000","doi-asserted-by":"crossref","unstructured":"Netchine, I., Sobrier, M. L., Krude, H., Schnabel, D., Maghnie, M., Marcos, E., Duriez, B., Cacheux, V., Moers, A., Goossens, M. et al. (2000). Mutations in LHX3 result in a new syndrome revealed by combined pituitary hormone deficiency. Nat. Genet.25, 182-186.","DOI":"10.1038\/76041"},{"key":"2021042604130223800_PARKS-ETAL-1999","doi-asserted-by":"crossref","unstructured":"Parks, J. S., Brown, M. R., Hurley, D. L., Phelps, C. J. and Wajnrajch, M. P. (1999). Heritable disorders of pituitary development. J. Clin. Endocrinol. Metab.84, 4362-4370.","DOI":"10.1210\/jc.84.12.4362"},{"key":"2021042604130223800_PIPER-ETAL-1999","doi-asserted-by":"crossref","unstructured":"Piper, D. E., Batchelor, A. H., Chang, C. P., Cleary, M. L. and Wolberger, C. (1999). Structure of a HoxB1-Pbx1 heterodimer bound to DNA: role of the hexapeptide and a fourth homeodomain helix in complex formation. Cell96, 587-597.","DOI":"10.1016\/S0092-8674(00)80662-5"},{"key":"2021042604130223800_SCHIER-AND-GEHRING-1992","doi-asserted-by":"crossref","unstructured":"Schier, A. F. and Gehring, W. J. (1992). Direct homeodomain-DNA interaction in the autoregulation of the fushi tarazu gene. Nature356, 804-807.","DOI":"10.1038\/356804a0"},{"key":"2021042604130223800_SMITH-ETAL-1988","doi-asserted-by":"crossref","unstructured":"Smith, A. G., Heath, J. K., Donaldson, D. D., Wong, G. G., Moreau, J., Stahl, M. and Rogers, D. (1988). Inhibition of pluripotential embryonic stem cell differentiation by purified polypeptides. Nature336, 688-690.","DOI":"10.1038\/336688a0"},{"key":"2021042604130223800_SMITH-AND-JAYNES-1996","doi-asserted-by":"crossref","unstructured":"Smith, S. T. and Jaynes, J. B. (1996). A conserved region of engrailed, shared among all en-, gsc-, Nk1-, Nk2- and msh-class homeoproteins, mediates active transcriptional repression in vivo. Development122, 3141-3150.","DOI":"10.1242\/dev.122.10.3141"},{"key":"2021042604130223800_SORNSON-ETAL-1996","doi-asserted-by":"crossref","unstructured":"Sornson, M. W., Wu, W., Dasen, J. S., Flynn, S. E., Norman, D. J., O\u2019Connell, S. M., Gukovsky, I., Carriere, C., Ryan, A. K., Miller, A. P. et al. (1996). Pituitary lineage determination by the Prophet of Pit-1 homeodomain factor defective in Ames dwarfism. Nature384, 327-333.","DOI":"10.1038\/384327a0"},{"key":"2021042604130223800_TADA-ETAL-1998","doi-asserted-by":"crossref","unstructured":"Tada, M., Casey, E. S., Fairclough, L. and Smith, J. C. (1998). Bix1, a direct target of Xenopus T-box genes, causes formation of ventral mesoderm and endoderm. Development125, 3997-4006.","DOI":"10.1242\/dev.125.20.3997"},{"key":"2021042604130223800_THOMAS-AND-BEDDINGTON-1996","doi-asserted-by":"crossref","unstructured":"Thomas, P. and Beddington, R. (1996). Anterior primitive endoderm may be responsible for patterning the anterior neural plate in the mouse embryo. Curr. Biol.6, 1487-1496.","DOI":"10.1016\/S0960-9822(96)00753-1"},{"key":"2021042604130223800_THOMAS-ETAL-2001","doi-asserted-by":"crossref","unstructured":"Thomas, P. Q., Dattani, M. T., Brickman, J. M., McNay, D., Warne, G., Zacharin, M., Cameron, F., Hurst, J., Woods, K., Dunger, D. et al. (2001). Heterozygous HESX1 mutations associated with isolated congenital pituitary hypoplasia and septo-optic dysplasia. Hum. Mol. Genet.10, 39-45.","DOI":"10.1093\/hmg\/10.1.39"},{"key":"2021042604130223800_TOLKUNOVA-ETAL-1998","doi-asserted-by":"crossref","unstructured":"Tolkunova, E. N., Fujioka, M., Kobayashi, M., Deka, D. and Jaynes, J. B. (1998). Two distinct types of repression domain in engrailed: one interacts with the groucho corepressor and is preferentially active on integrated target genes. Mol. Cell Biol.18, 2804-2814.","DOI":"10.1128\/MCB.18.5.2804"},{"key":"2021042604130223800_TREISMAN-ETAL-1989","doi-asserted-by":"crossref","unstructured":"Treisman, J., Gonczy, P., Vashishtha, M., Harris, E. and Desplan, C. (1989). A single amino acid can determine the DNA binding specificity of homeodomain proteins. Cell59, 553-562.","DOI":"10.1016\/0092-8674(89)90038-X"},{"key":"2021042604130223800_VALENTINE-ETAL-1998","doi-asserted-by":"crossref","unstructured":"Valentine, S. A., Chen, G., Shandala, T., Fernandez, J., Mische, S., Saint, R. and Courey, A. J. (1998). Dorsal-mediated repression requires the formation of a multiprotein repression complex at the ventral silencer. Mol. Cell Biol.18, 6584-6594.","DOI":"10.1128\/MCB.18.11.6584"},{"key":"2021042604130223800_WALES-AND-QUARRELL-1996","doi-asserted-by":"crossref","unstructured":"Wales, J. K. and Quarrell, O. W. (1996). Evidence for possible Mendelian inheritance of septo-optic dysplasia. Acta Paediatr.85, 391-392.","DOI":"10.1111\/j.1651-2227.1996.tb14044.x"},{"key":"2021042604130223800_WILSON-ETAL-1993","doi-asserted-by":"crossref","unstructured":"Wilson, D., Sheng, G., Lecuit, T., Dostatni, N. and Desplan, C. (1993). Cooperative dimerization of paired class homeo domains on DNA. Genes Dev.7, 2120-2134.","DOI":"10.1101\/gad.7.11.2120"},{"key":"2021042604130223800_WINNIER-ETAL-1999","doi-asserted-by":"crossref","unstructured":"Winnier, A. R., Meir, J. Y., Ross, J. M., Tavernarakis, N., Driscoll, M., Ishihara, T., Katsura, I. and Miller, D. M., 3rd (1999). UNC-4\/UNC-37-dependent repression of motor neuron-specific genes controls synaptic choice in Caenorhabditis elegans. Genes Dev.13, 2774-2786.","DOI":"10.1101\/gad.13.21.2774"},{"key":"2021042604130223800_WOLBERGER-1996","doi-asserted-by":"crossref","unstructured":"Wolberger, C. (1996). Homeodomain interactions. Curr. Opin. Struct. Biol.6, 62-68.","DOI":"10.1016\/S0959-440X(96)80096-0"},{"key":"2021042604130223800_XU-ETAL-1998","doi-asserted-by":"crossref","unstructured":"Xu, L., Lavinsky, R. M., Dasen, J. S., Flynn, S. E., McInerney, E. M., Mullen, T. M., Heinzel, T., Szeto, D., Korzus, E., Kurokawa, R. et al. (1998). Signal-specific co-activator domain requirements for Pit-1 activation. Nature395, 301-306.","DOI":"10.1038\/26270"}],"container-title":["Development"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/journals.biologists.com\/dev\/article-pdf\/128\/24\/5189\/1138780\/5189.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dev\/article-pdf\/128\/24\/5189\/1138780\/5189.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,8,29]],"date-time":"2024-08-29T07:08:41Z","timestamp":1724915321000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.biologists.com\/dev\/article\/128\/24\/5189\/41586\/Molecular-effects-of-novel-mutations-in-Hesx1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2001,12,15]]},"references-count":44,"journal-issue":{"issue":"24","published-print":{"date-parts":[[2001,12,15]]}},"URL":"https:\/\/doi.org\/10.1242\/dev.128.24.5189","relation":{},"ISSN":["1477-9129","0950-1991"],"issn-type":[{"value":"1477-9129","type":"electronic"},{"value":"0950-1991","type":"print"}],"subject":[],"published":{"date-parts":[[2001,12,15]]}}}