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Gene Review

HESX1  -  HESX homeobox 1

Homo sapiens

Synonyms: ANF, CPHD5, HANF, Homeobox expressed in ES cells 1, Homeobox protein ANF, ...
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Disease relevance of HESX1


High impact information on HESX1

  • Mutations in the homeobox gene HESX1/Hesx1 associated with septo-optic dysplasia in human and mouse [7].
  • These data suggest an important role for Hesx1/HESX1 in forebrain, midline and pituitary development in mouse and human [7].
  • Two siblings with SOD were homozygous for an Arg53Cys missense mutation within the HESX1 homeodomain which destroyed its ability to bind target DNA [7].
  • Thus, the novel pituitary phenotype highlighted here appears to be a specific consequence of the inability of HESX1 to recruit Groucho-related corepressors, suggesting that other molecular mechanisms govern HESX1 function in the forebrain [8].
  • A homozygous mutation in HESX1 is associated with evolving hypopituitarism due to impaired repressor-corepressor interaction [8].

Biological context of HESX1

  • DESIGN AND PATIENTS: The three coding exons of PROP1, and six exons of POUF-1 in 27 children from 26 families with CPHD, and three exons of HESX1 in 23 children from 22 families with SOD were directly sequenced from a well-characterized regional cohort [9].
  • Sporadic heterozygous frameshift mutation of HESX1 causing pituitary and optic nerve hypoplasia and combined pituitary hormone deficiency in a Japanese patient [10].
  • Segregation analysis of a haplotype spanning 6.1 cM, which contains the HESX1 locus, indicated that only one HESX1 mutation was present in the families containing the C509T and A541G mutations [11].
  • We cloned and sequenced the human homologue HESX1 and screened for mutations in affected individuals using single-stranded conformational polymorphism analysis, followed by cloning and sequencing of any exons which showed a band shift [12].
  • This rare developmental anomaly of midline brain structures can result from different pathogenetical events, including mutations of the homeo box gene HESX1, recently suggested as the etiological cause at least in a subset of patients [13].

Anatomical context of HESX1

  • MATERIALS AND METHODS: A total of 102 lymph node positive patients from the RPX series at Ulm University were evaluated [14].
  • Sinus of Valsalva aneurysm (SVA) is a rare congenital lesion described first in 1840 by John Thurnam (Cited by Boutefou JM, Moret PR, Hahn C, Hanf E. Aneurysms of the sinus of Valsalva: report of seven cases and review of the literature. Am J Med 1978;65:18-24) [15].

Associations of HESX1 with chemical compounds

  • Following routine coronary arteriography, surface irregularities and thrombogenesis of the inner and outer wall of six Ducor polyurethane and six RPX polyethylene coronary catheters were studied by scanning electron microscopy [16].
  • RPX success required a postoperative PSA that was undetectable (PSA <0.2 ng/ml by the Hybritech or Abbott IMx technics) [17].

Regulatory relationships of HESX1


Other interactions of HESX1

  • Expression of the HESX1 gene precedes expression of PROP1 and PIT1, and it is much more widespread [1].
  • More recently mutations in the HESX1, the LHX3 and LHX4 transcription factor genes have also been described as a cause in patients with CPHD [18].
  • Rarely, heterozygous mutations in the gene encoding for HESX-1 gene (HESX-1) may cause autosomal-dominant IGHD, with penetrance that has been shown to be variable in both humans and mice [19].
  • Accordingly, we have now scanned for HESX1 mutations in 228 patients with a broad spectrum of congenital pituitary defects, ranging in severity from isolated growth hormone deficiency to SOD with panhypopituitarism [11].

Analytical, diagnostic and therapeutic context of HESX1

  • 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 [3].
  • Patients and design Sixty-two patients with hypopituitarism associated with EPL were submitted to evaluation of pituitary function, analysis of MRI with EPL location and molecular analysis of LHX4 and HESX1 using polymerase chain reaction (PCR), digestion with restriction enzyme and automatic sequencing [20].
  • BACKGROUND: The further course of prostate cancer (PC) after radical prostatectomy (RPX) is decisively influenced by the local tumor stage [21].
  • Considering the low detection rates in BPH patients, the method may also be suitable for patient monitoring after RPX and could thus play an important role in deciding on early radiotherapy or even hormone ablation therapy [22].
  • The impact of R53C substitution on Hesx-1 homeodomain structure, stability, and DNA-binding properties was analyzed by using a combination of NMR spectroscopy, molecular modeling and circular dichroism experiments [23].


  1. Heritable disorders of pituitary development. Parks, J.S., Brown, M.R., Hurley, D.L., Phelps, C.J., Wajnrajch, M.P. J. Clin. Endocrinol. Metab. (1999) [Pubmed]
  2. Enhanced repression by HESX1 as a cause of hypopituitarism and septooptic dysplasia. Cohen, R.N., Cohen, L.E., Botero, D., Yu, C., Sagar, A., Jurkiewicz, M., Radovick, S. J. Clin. Endocrinol. Metab. (2003) [Pubmed]
  3. Molecular effects of novel mutations in Hesx1/HESX1 associated with human pituitary disorders. Brickman, J.M., Clements, M., Tyrell, R., McNay, D., Woods, K., Warner, J., Stewart, A., Beddington, R.S., Dattani, M. Development (2001) [Pubmed]
  4. HESX1 expression in human normal pituitaries and pituitary adenomas. Mantovani, G., Asteria, C., Pellegrini, C., Bosari, S., Alberti, L., Bondioni, S., Peverelli, E., Spada, A., Beck-Peccoz, P. Mol. Cell. Endocrinol. (2006) [Pubmed]
  5. Alu-element insertion in the homeodomain of HESX1 and aplasia of the anterior pituitary. Sobrier, M.L., Netchine, I., Heinrichs, C., Thibaud, N., Vié-Luton, M.P., Van Vliet, G., Amselem, S. Hum. Mutat. (2005) [Pubmed]
  6. HESX1 mutations are an uncommon cause of septooptic dysplasia and hypopituitarism. McNay, D.E., Turton, J.P., Kelberman, D., Woods, K.S., Brauner, R., Papadimitriou, A., Keller, E., Keller, A., Haufs, N., Krude, H., Shalet, S.M., Dattani, M.T. J. Clin. Endocrinol. Metab. (2007) [Pubmed]
  7. Mutations in the homeobox gene HESX1/Hesx1 associated with septo-optic dysplasia in human and mouse. Dattani, M.T., Martinez-Barbera, J.P., Thomas, P.Q., Brickman, J.M., Gupta, R., Mårtensson, I.L., Toresson, H., Fox, M., Wales, J.K., Hindmarsh, P.C., Krauss, S., Beddington, R.S., Robinson, I.C. Nat. Genet. (1998) [Pubmed]
  8. A homozygous mutation in HESX1 is associated with evolving hypopituitarism due to impaired repressor-corepressor interaction. Carvalho, L.R., Woods, K.S., Mendonca, B.B., Marcal, N., Zamparini, A.L., Stifani, S., Brickman, J.M., Arnhold, I.J., Dattani, M.T. J. Clin. Invest. (2003) [Pubmed]
  9. Mutation analysis of POUF-1, PROP-1 and HESX-1 show low frequency of mutations in children with sporadic forms of combined pituitary hormone deficiency and septo-optic dysplasia. Rainbow, L.A., Rees, S.A., Shaikh, M.G., Shaw, N.J., Cole, T., Barrett, T.G., Kirk, J.M. Clin. Endocrinol. (Oxf) (2005) [Pubmed]
  10. Sporadic heterozygous frameshift mutation of HESX1 causing pituitary and optic nerve hypoplasia and combined pituitary hormone deficiency in a Japanese patient. Tajima, T., Hattorri, T., Nakajima, T., Okuhara, K., Sato, K., Abe, S., Nakae, J., Fujieda, K. J. Clin. Endocrinol. Metab. (2003) [Pubmed]
  11. Heterozygous HESX1 mutations associated with isolated congenital pituitary hypoplasia and septo-optic dysplasia. Thomas, P.Q., Dattani, M.T., Brickman, J.M., McNay, D., Warne, G., Zacharin, M., Cameron, F., Hurst, J., Woods, K., Dunger, D., Stanhope, R., Forrest, S., Robinson, I.C., Beddington, R.S. Hum. Mol. Genet. (2001) [Pubmed]
  12. Molecular genetics of septo-optic dysplasia. Dattani, M.L., Martinez-Barbera, J., Thomas, P.Q., Brickman, J.M., Gupta, R., Wales, J.K., Hindmarsh, P.C., Beddington, R.S., Robinson, I.C. Horm. Res. (2000) [Pubmed]
  13. Septo-optic dysplasia with digital anomalies associated with maternal multidrug abuse during pregnancy. Orrico, A., Galli, L., Zappella, M., Monti, L., Vatti, G.P., Venturi, C., Hayek, G. Eur. J. Neurol. (2002) [Pubmed]
  14. Comparison of external radiation therapy vs radical prostatectomy in lymph node positive prostate cancer patients. Kuefer, R., Volkmer, B.G., Loeffler, M., Shen, R.L., Kempf, L., Merseburger, A.S., Gschwend, J.E., Hautmann, R.E., Sandler, H.M., Rubin, M.A. Prostate Cancer Prostatic Dis. (2004) [Pubmed]
  15. Rare cause of right heart failure: contained rupture of a sinus of Valsalva aneurysm associated intraventricular septal aneurysm. Mookadam, F., Haley, J., Mendrick, E. European journal of echocardiography : the journal of the Working Group on Echocardiography of the European Society of Cardiology. (2005) [Pubmed]
  16. Scanning electron microscopy of surface irregularities and thrombogenesis of polyurethane and polyethylene coronary catheters. Bourassa, M.G., Cantin, M., Sandborn, E.B., Pederson, E. Circulation (1976) [Pubmed]
  17. Assessment of relative tumor burden in patients with clinical T1c prostate cancer treated with either external beam or radical prostatectomy. Hintz, B.L., Murphy, J.S., Kaswick, J.A., Bellman, G.C., Ruel, C.J., Kagan, A.R. Am. J. Clin. Oncol. (1999) [Pubmed]
  18. Adrenocorticotrope deficiency with clinical evidence for late onset in combined pituitary hormone deficiency caused by a homozygous 301-302delAG mutation of the PROP1 gene. Lamesch, C., Neumann, S., Pfäffle, R., Kiess, W., Paschke, R. Pituitary (2002) [Pubmed]
  19. Autosomal-dominant isolated growth hormone deficiency (IGHD type II) with normal GH-1 gene. Fintini, D., Salvatori, R., Salemi, S., Otten, B., Ubertini, G., Cambiaso, P., Mullis, P.E. Horm. Res. (2006) [Pubmed]
  20. Hormonal, pituitary magnetic resonance, LHX4 and HESX1 evaluation in patients with hypopituitarism and ectopic posterior pituitary lobe. Melo, M.E., Marui, S., Carvalho, L.R., Arnhold, I.J., Leite, C.C., Mendon??a, B.B., Knoepfelmacher, M. Clin. Endocrinol. (Oxf) (2007) [Pubmed]
  21. Molecular staging of surgical margins after radical prostatectomy by detection of telomerase activity. Straub, B., Müller, M., Krause, H., Goessl, C., Schrader, M., Heicappell, R., Miller, K. Prostate (2001) [Pubmed]
  22. Quantitative real-time rt-PCR for detection of circulating prostate-specific antigen mRNA using sequence-specific oligonucleotide hybridization probes in prostate cancer patients. Straub, B., Müller, M., Krause, H., Schrader, M., Miller, K. Oncology (2003) [Pubmed]
  23. The impact of R53C mutation on the three-dimensional structure, stability, and DNA-binding properties of the human Hesx-1 homeodomain. de la Mata, I., Garcia, J.L., González, C., Menéndez, M., Cañada, J., Jiménez-Barbero, J., Asensio, J.L. Chembiochem (2002) [Pubmed]
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