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Gene Review

SHH  -  sonic hedgehog

Homo sapiens

Synonyms: HHG-1, HHG1, HLP3, HPE3, MCOPCB5, ...
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Disease relevance of SHH


Psychiatry related information on SHH


High impact information on SHH

  • Several of these mutations encode truncated proteins that are unable to export the GLI transcription factor from nucleus to cytoplasm, resulting in the activation of SHH signaling [1].
  • We report here that a subset of children with medulloblastoma carry germline and somatic mutations in SUFU (encoding the human suppressor of fused) of the SHH pathway, accompanied by loss of heterozygosity of the wildtype allele [1].
  • The sonic hedgehog (SHH) signaling pathway directs the embryonic development of diverse organisms and is disrupted in a variety of malignancies [1].
  • BMP7 acts directly on neural cells, modifying their response to SHH so that they differentiate into rostral diencephalic ventral midline cells rather than floor plate cells [9].
  • However, prechordal mesoderm also expresses BMP7 whose function is required coordinately with SHH to induce rostral diencephalic ventral midline cells [9].

Chemical compound and disease context of SHH


Biological context of SHH


Anatomical context of SHH


Associations of SHH with chemical compounds

  • This is the first instance in humans where SHH mutations in the domain responsible for autocatalytic cleavage and cholesterol modification of the N-terminal signaling domain of the protein have been observed [16].
  • The results revealed that cyclopamine, alone or at a lower concentration in combination with gefitinib, inhibited the growth of sonic hedgehog- (SHH), epidermal growth factor- (EGF) and serum-stimulated androgen-sensitive LNCaP-C33 and LNCaP-LN3 and androgen-independent LNCaP-C81, DU145 and PC3 cells [17].
  • The SHH signaling pathway is an important developmental pathway, and ptc protein (PTC) is a suppressive component serving as a receptor for the secreted SHH [18].
  • Immunohistochemical studies showed intact dopaminergic pathways in the mesencephalon, suggesting that midbrain dopamine neuron induction appears to require only one functioning SHH allele [19].
  • Sonic hedgehog (SHH) is a secreted glycoprotein that has a major role in the developing cerebellum [20].

Physical interactions of SHH


Regulatory relationships of SHH

  • However, SHH induced GLI-dependent promoter activity in normal urothelial cells [24].
  • SHH regulates growth and differentiation within gastric mucosa through autocrine loop and FOXL1-mediated epithelial-mesenchymal interaction [13].
  • Sonic hedgehog (SHH) is expressed throughout axial mesoderm and is required for the induction of both rostral diencephalic ventral midline cells and floor plate [9].
  • FOXM1 gene is up-regulated in pancreatic cancer and basal cell carcinoma due to the transcriptional regulation by Sonic Hedgehog (SHH) pathway [25].
  • Perlecan is a proteoglycan that regulates extracellular and stromal accessibility to growth factors such as SHH, thus allowing for the maintenance of SHH signaling under growth factor limiting conditions [23].

Other interactions of SHH

  • CONCLUSION: Both SHH and DHH signaling components were detected during human fetal prostate development [26].
  • They include Sonic hedgehog (SHH), ZIC2, and SIX3 [27].
  • We noted that high levels of SHH appear almost regularly, especially in dermoids, usually accompanied by increased expression of SMO [28].
  • We identified three novel mutations: two were missense mutations of the SHH gene (Cys183-->Phe; His140-->Pro); the third mutation was a 2-bp deletion in the zinc-finger region of the ZIC2 gene [29].
  • Differential epithelial expression of SHH and FOXF1 in usual and nonspecific interstitial pneumonia [30].

Analytical, diagnostic and therapeutic context of SHH


  1. Mutations in SUFU predispose to medulloblastoma. Taylor, M.D., Liu, L., Raffel, C., Hui, C.C., Mainprize, T.G., Zhang, X., Agatep, R., Chiappa, S., Gao, L., Lowrance, A., Hao, A., Goldstein, A.M., Stavrou, T., Scherer, S.W., Dura, W.T., Wainwright, B., Squire, J.A., Rutka, J.T., Hogg, D. Nat. Genet. (2002) [Pubmed]
  2. Inhibition of prostate cancer proliferation by interference with SONIC HEDGEHOG-GLI1 signaling. Sanchez, P., Hernández, A.M., Stecca, B., Kahler, A.J., DeGueme, A.M., Barrett, A., Beyna, M., Datta, M.W., Datta, S., Ruiz i Altaba, A. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  3. Missense mutations in SMOH in sporadic basal cell carcinomas of the skin and primitive neuroectodermal tumors of the central nervous system. Reifenberger, J., Wolter, M., Weber, R.G., Megahed, M., Ruzicka, T., Lichter, P., Reifenberger, G. Cancer Res. (1998) [Pubmed]
  4. Expression of Sonic hedgehog (SHH) signaling molecules in ameloblastomas. Kumamoto, H., Ohki, K., Ooya, K. J. Oral Pathol. Med. (2004) [Pubmed]
  5. Expression of the Sonic hedgehog (SHH ) gene during early human development and phenotypic expression of new mutations causing holoprosencephaly. Odent, S., Atti-Bitach, T., Blayau, M., Mathieu, M., Aug, J., Delezo de, A.L., Gall, J.Y., Le Marec, B., Munnich, A., David, V., Vekemans, M. Hum. Mol. Genet. (1999) [Pubmed]
  6. Two critical periods of Sonic Hedgehog signaling required for the specification of motor neuron identity. Ericson, J., Morton, S., Kawakami, A., Roelink, H., Jessell, T.M. Cell (1996) [Pubmed]
  7. Behavioural and immunohistochemical changes following supranigral administration of sonic hedgehog in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated common marmosets. Dass, B., Iravani, M.M., Jackson, M.J., Engber, T.M., Galdes, A., Jenner, P. Neuroscience (2002) [Pubmed]
  8. Wide phenotypic variability in families with holoprosencephaly and a sonic hedgehog mutation. Hehr, U., Gross, C., Diebold, U., Wahl, D., Beudt, U., Heidemann, P., Hehr, A., Mueller, D. Eur. J. Pediatr. (2004) [Pubmed]
  9. Cooperation of BMP7 and SHH in the induction of forebrain ventral midline cells by prechordal mesoderm. Dale, J.K., Vesque, C., Lints, T.J., Sampath, T.K., Furley, A., Dodd, J., Placzek, M. Cell (1997) [Pubmed]
  10. Epithelial expression of SHH signaling pathway in odontogenic tumors. Zhang, L., Chen, X.M., Sun, Z.J., Bian, Z., Fan, M.W., Chen, Z. Oral Oncol. (2006) [Pubmed]
  11. Molecular abnormalities in pediatric embryonal brain tumors--analysis of loss of heterozygosity on chromosomes 1, 5, 9, 10, 11, 16, 17 and 22. Zakrzewska, M., Rieske, P., Debiec-Rychter, M., Zakrzewski, K., Polis, L., Fiks, T., Liberski, P.P. Clin. Neuropathol. (2004) [Pubmed]
  12. SONIC HEDGEHOG mutations causing human holoprosencephaly impair neural patterning activity. Schell-Apacik, C., Rivero, M., Knepper, J.L., Roessler, E., Muenke, M., Ming, J.E. Hum. Genet. (2003) [Pubmed]
  13. Hedgehog signaling pathway and gastric cancer. Katoh, Y., Katoh, M. Cancer Biol. Ther. (2005) [Pubmed]
  14. Hh pathway expression in human gut tissues and in inflammatory gut diseases. Nielsen, C.M., Williams, J., van den Brink, G.R., Lauwers, G.Y., Roberts, D.J. Lab. Invest. (2004) [Pubmed]
  15. SHH mutation is associated with solitary median maxillary central incisor: a study of 13 patients and review of the literature. Nanni, L., Ming, J.E., Du, Y., Hall, R.K., Aldred, M., Bankier, A., Muenke, M. Am. J. Med. Genet. (2001) [Pubmed]
  16. Mutations in the C-terminal domain of Sonic Hedgehog cause holoprosencephaly. Roessler, E., Belloni, E., Gaudenz, K., Vargas, F., Scherer, S.W., Tsui, L.C., Muenke, M. Hum. Mol. Genet. (1997) [Pubmed]
  17. Cytotoxic effects induced by a combination of cyclopamine and gefitinib, the selective hedgehog and epidermal growth factor receptor signaling inhibitors, in prostate cancer cells. Mimeault, M., Moore, E., Moniaux, N., Hénichart, J.P., Depreux, P., Lin, M.F., Batra, S.K. Int. J. Cancer (2006) [Pubmed]
  18. Expression of sonic hedgehog signal transducers, patched and smoothened, in human basal cell carcinoma. Tojo, M., Mori, T., Kiyosawa, H., Honma, Y., Tanno, Y., Kanazawa, K.Y., Yokoya, S., Kaneko, F., Wanaka, A. Pathol. Int. (1999) [Pubmed]
  19. Holoprosencephaly, sacral anomalies, and situs ambiguus in an infant with partial monosomy 7q/trisomy 2p and SHH and HLXB9 haploinsufficiency.. Nowaczyk, M.J., Huggins, M.J., Tomkins, D.J., Rossi, E., Ramsay, J.A., Woulfe, J., Scherer, S.W., Belloni, E. Clin. Genet. (2000) [Pubmed]
  20. GLI3 is not mutated commonly in sporadic medulloblastomas. Erez, A., Ilan, T., Amariglio, N., Muler, I., Brok-Simoni, F., Rechavi, G., Izraeli, S. Cancer (2002) [Pubmed]
  21. Mutations in PATCHED-1, the receptor for SONIC HEDGEHOG, are associated with holoprosencephaly. Ming, J.E., Kaupas, M.E., Roessler, E., Brunner, H.G., Golabi, M., Tekin, M., Stratton, R.F., Sujansky, E., Bale, S.J., Muenke, M. Hum. Genet. (2002) [Pubmed]
  22. Inhibition of SHH signaling pathway: Molecular treatment strategy of odontogenic keratocyst. Zhang, L., Sun, Z.J., Zhao, Y.F., Bian, Z., Fan, M.W., Chen, Z. Med. Hypotheses (2006) [Pubmed]
  23. Perlecan, a candidate gene for the CAPB locus, regulates prostate cancer cell growth via the Sonic Hedgehog pathway. Datta, M.W., Hernandez, A.M., Schlicht, M.J., Kahler, A.J., DeGueme, A.M., Dhir, R., Shah, R.B., Farach-Carson, C., Barrett, A., Datta, S. Mol. Cancer (2006) [Pubmed]
  24. Hedgehog signaling in normal urothelial cells and in urothelial carcinoma cell lines. Thievessen, I., Wolter, M., Prior, A., Seifert, H.H., Schulz, W.A. J. Cell. Physiol. (2005) [Pubmed]
  25. Human FOX gene family (Review). Katoh, M., Katoh, M. Int. J. Oncol. (2004) [Pubmed]
  26. Sonic and desert hedgehog signaling in human fetal prostate development. Zhu, G., Zhau, H.E., He, H., Zhang, L., Shehata, B., Wang, X., Cerwinka, W.H., Elmore, J., He, D. Prostate (2007) [Pubmed]
  27. Molecular mechanisms of holoprosencephaly. Wallis, D.E., Muenke, M. Mol. Genet. Metab. (1999) [Pubmed]
  28. Role of the hedgehog/patched signaling pathway in oncogenesis: a new polymorphism in the PTCH gene in ovarian fibroma. Levanat, S., Musani, V., Komar, A., Oreskovic, S. Ann. N. Y. Acad. Sci. (2004) [Pubmed]
  29. Identification of novel mutations in SHH and ZIC2 in a South American (ECLAMC) population with holoprosencephaly. Orioli, I.M., Castilla, E.E., Ming, J.E., Nazer, J., Burle de Aguiar, M.J., Llerena, J.C., Muenke, M. Hum. Genet. (2001) [Pubmed]
  30. Differential epithelial expression of SHH and FOXF1 in usual and nonspecific interstitial pneumonia. Coon, D.R., Roberts, D.J., Loscertales, M., Kradin, R. Exp. Mol. Pathol. (2006) [Pubmed]
  31. Functional characterization of sonic hedgehog mutations associated with holoprosencephaly. Traiffort, E., Dubourg, C., Faure, H., Rognan, D., Odent, S., Durou, M.R., David, V., Ruat, M. J. Biol. Chem. (2004) [Pubmed]
  32. Mutational analysis of the Sonic Hedgehog gene in 220 newborns with oral clefts in a South American (ECLAMC) population. Orioli, I.M., Vieira, A.R., Castilla, E.E., Ming, J.E., Muenke, M. Am. J. Med. Genet. (2002) [Pubmed]
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