6n7k

Structural highlights

Disease

[PTC1_HUMAN] Semilobar holoprosencephaly;Monosomy 9q22.3;Alobar holoprosencephaly;Microform holoprosencephaly;Septopreoptic holoprosencephaly;Gorlin syndrome;Lobar holoprosencephaly;Midline interhemispheric variant of holoprosencephaly. The disease may be caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. [SHH_HUMAN] Defects in SHH are the cause of microphthalmia isolated with coloboma type 5 (MCOPCB5) [MIM:611638]. Microphthalmia is a clinically heterogeneous disorder of eye formation, ranging from small size of a single eye to complete bilateral absence of ocular tissues. Ocular abnormalities like opacities of the cornea and lens, scaring of the retina and choroid, cataract and other abnormalities like cataract may also be present. Ocular colobomas are a set of malformations resulting from abnormal morphogenesis of the optic cup and stalk, and the fusion of the fetal fissure (optic fissure).^[1] Defects in SHH are the cause of holoprosencephaly type 3 (HPE3) [MIM:142945]. Holoprosencephaly (HPE) [MIM:236100] is the most common structural anomaly of the brain, in which the developing forebrain fails to correctly separate into right and left hemispheres. Holoprosencephaly is genetically heterogeneous and associated with several distinct facies and phenotypic variability. The majority of HPE3 cases are apparently sporadic, although clear examples of autosomal dominant inheritance have been described. Interestingly, up to 30% of obligate carriers of HPE3 gene in autosomal dominant pedigrees are clinically unaffected.^{[2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13]} Defects in SHH are a cause of solitary median maxillary central incisor (SMMCI) [MIM:147250]. SMMCI is a rare dental anomaly characterized by the congenital absence of one maxillary central incisor.^{[14] [15]} Defects in SHH are the cause of triphalangeal thumb-polysyndactyly syndrome (TPTPS) [MIM:174500]. TPTPS is an autosomal dominant syndrome characterized by a wide spectrum of pre- and post-axial abnormalities due to altered SHH expression pattern during limb development. TPTPS mutations have been mapped to the 7q36 locus in the LMBR1 gene which contains in its intron 5 a long-range cis-regulatory element of SHH expression.^[16]

Function

[PTC1_HUMAN] Acts as a receptor for sonic hedgehog (SHH), indian hedgehog (IHH) and desert hedgehog (DHH). Associates with the smoothened protein (SMO) to transduce the hedgehog's proteins signal. Seems to have a tumor suppressor function, as inactivation of this protein is probably a necessary, if not sufficient step for tumorigenesis.^[17] [SHH_HUMAN] Binds to the patched (PTC) receptor, which functions in association with smoothened (SMO), to activate the transcription of target genes. In the absence of SHH, PTC represses the constitutive signaling activity of SMO. Also regulates another target, the gli oncogene. Intercellular signal essential for a variety of patterning events during development: signal produced by the notochord that induces ventral cell fate in the neural tube and somites, and the polarizing signal for patterning of the anterior-posterior axis of the developing limb bud. Displays both floor plate- and motor neuron-inducing activity. The threshold concentration of N-product required for motor neuron induction is 5-fold lower than that required for floor plate induction (By similarity).

References

1. ↑ Schimmenti LA, de la Cruz J, Lewis RA, Karkera JD, Manligas GS, Roessler E, Muenke M. Novel mutation in sonic hedgehog in non-syndromic colobomatous microphthalmia. Am J Med Genet A. 2003 Jan 30;116A(3):215-21. PMID:12503095 doi:10.1002/ajmg.a.10884
2. ↑ Roessler E, Belloni E, Gaudenz K, Jay P, Berta P, Scherer SW, Tsui LC, Muenke M. Mutations in the human Sonic Hedgehog gene cause holoprosencephaly. Nat Genet. 1996 Nov;14(3):357-60. PMID:8896572 doi:10.1038/ng1196-357
3. ↑ Roessler E, Belloni E, Gaudenz K, Vargas F, Scherer SW, Tsui LC, Muenke M. Mutations in the C-terminal domain of Sonic Hedgehog cause holoprosencephaly. Hum Mol Genet. 1997 Oct;6(11):1847-53. PMID:9302262
4. ↑ Odent S, Atti-Bitach T, Blayau M, Mathieu M, Aug J, Delezo de AL, Gall JY, Le Marec B, Munnich A, David V, Vekemans M. Expression of the Sonic hedgehog (SHH ) gene during early human development and phenotypic expression of new mutations causing holoprosencephaly. Hum Mol Genet. 1999 Sep;8(9):1683-9. PMID:10441331
5. ↑ Nanni L, Ming JE, Bocian M, Steinhaus K, Bianchi DW, Die-Smulders C, Giannotti A, Imaizumi K, Jones KL, Campo MD, Martin RA, Meinecke P, Pierpont ME, Robin NH, Young ID, Roessler E, Muenke M. The mutational spectrum of the sonic hedgehog gene in holoprosencephaly: SHH mutations cause a significant proportion of autosomal dominant holoprosencephaly. Hum Mol Genet. 1999 Dec;8(13):2479-88. PMID:10556296
6. ↑ Orioli IM, Castilla EE, Ming JE, Nazer J, Burle de Aguiar MJ, Llerena JC, Muenke M. Identification of novel mutations in SHH and ZIC2 in a South American (ECLAMC) population with holoprosencephaly. Hum Genet. 2001 Jul;109(1):1-6. PMID:11479728
7. ↑ Hehr U, Gross C, Diebold U, Wahl D, Beudt U, Heidemann P, Hehr A, Mueller D. Wide phenotypic variability in families with holoprosencephaly and a sonic hedgehog mutation. Eur J Pediatr. 2004 Jul;163(7):347-52. Epub 2004 Apr 24. PMID:15107988 doi:10.1007/s00431-004-1459-0
8. ↑ Dubourg C, Lazaro L, Pasquier L, Bendavid C, Blayau M, Le Duff F, Durou MR, Odent S, David V. Molecular screening of SHH, ZIC2, SIX3, and TGIF genes in patients with features of holoprosencephaly spectrum: Mutation review and genotype-phenotype correlations. Hum Mutat. 2004 Jul;24(1):43-51. PMID:15221788 doi:10.1002/humu.20056
9. ↑ El-Jaick KB, Brunoni D, Castilla EE, Moreira MA, Orioli IM. SHH Ile111Asp in alobar holoprosencephaly in a proposita, whose mother had only a solitary median maxillary incisor. Am J Med Genet A. 2005 Aug 1;136A(4):345. PMID:15942952 doi:10.1002/ajmg.a.30624
10. ↑ Ribeiro LA, Richieri-Costa A. Single median maxillary central incisor, hypophyseal tumor, and SHH mutation. Am J Med Genet A. 2005 Aug 1;136A(4):346-7. PMID:15942953 doi:10.1002/ajmg.a.30625
11. ↑ Maity T, Fuse N, Beachy PA. Molecular mechanisms of Sonic hedgehog mutant effects in holoprosencephaly. Proc Natl Acad Sci U S A. 2005 Nov 22;102(47):17026-31. Epub 2005 Nov 10. PMID:16282375 doi:10.1073/pnas.0507848102
12. ↑ Richieri-Costa A, Ribeiro LA. Holoprosencephaly-like phenotype: clinical and genetic perspectives. Am J Med Genet A. 2006 Dec 1;140(23):2587-93. PMID:17001669 doi:10.1002/ajmg.a.31378
13. ↑ Roessler E, El-Jaick KB, Dubourg C, Velez JI, Solomon BD, Pineda-Alvarez DE, Lacbawan F, Zhou N, Ouspenskaia M, Paulussen A, Smeets HJ, Hehr U, Bendavid C, Bale S, Odent S, David V, Muenke M. The mutational spectrum of holoprosencephaly-associated changes within the SHH gene in humans predicts loss-of-function through either key structural alterations of the ligand or its altered synthesis. Hum Mutat. 2009 Oct;30(10):E921-35. doi: 10.1002/humu.21090. PMID:19603532 doi:10.1002/humu.21090
14. ↑ Nanni L, Ming JE, Du Y, Hall RK, Aldred M, Bankier A, Muenke M. SHH mutation is associated with solitary median maxillary central incisor: a study of 13 patients and review of the literature. Am J Med Genet. 2001 Jul 22;102(1):1-10. PMID:11471164
15. ↑ Garavelli L, Zanacca C, Caselli G, Banchini G, Dubourg C, David V, Odent S, Gurrieri F, Neri G. Solitary median maxillary central incisor syndrome: clinical case with a novel mutation of sonic hedgehog. Am J Med Genet A. 2004 May 15;127A(1):93-5. PMID:15103725 doi:10.1002/ajmg.a.20685
16. ↑ Lettice LA, Heaney SJ, Purdie LA, Li L, de Beer P, Oostra BA, Goode D, Elgar G, Hill RE, de Graaff E. A long-range Shh enhancer regulates expression in the developing limb and fin and is associated with preaxial polydactyly. Hum Mol Genet. 2003 Jul 15;12(14):1725-35. PMID:12837695
17. ↑ Ma G, Yu J, Xiao Y, Chan D, Gao B, Hu J, He Y, Guo S, Zhou J, Zhang L, Gao L, Zhang W, Kang Y, Cheah KS, Feng G, Guo X, Wang Y, Zhou CZ, He L. Indian hedgehog mutations causing brachydactyly type A1 impair Hedgehog signal transduction at multiple levels. Cell Res. 2011 Sep;21(9):1343-57. doi: 10.1038/cr.2011.76. Epub 2011 May 3. PMID:21537345 doi:http://dx.doi.org/10.1038/cr.2011.76