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Identification of Sonic hedgehog as a candidate gene responsible for holoprosencephaly

Abstract

Holoprosencephaly (HPE) is a genetically and phenotypically heterogenous disorder involving the development of forebrain and midface, with an incidence of 1:16,000 live born and 1:250 induced abortions1. This disorder is associated with several distinct facies and phenotypic variability: in the most extreme cases, anophthalmia or cyclopia is evident along with a congenital absence of the mature nose. The less severe form features facial dysmorphia characterized by ocular hypertelorism, defects of the upper lip and/or nose, and absence of the olfactory nerves or corpus callosum. Several intermediate phenotypes involving both the brain and face have been described. One of the gene loci, HPE3, maps to the terminal band of chromosome 7. We have performed extensive physical mapping studies and established a critical interval for HPE3, and subsequently identified the sonic hedgehog (SHH) gene as the prime candidate for the disorder. SHH lies within 15–250 kilobases (kb) of chromosomal rearrangements associated with HPE, suggesting that a ‘position effect’ has an important role in the aetiology of HPE. As detailed in the accompanying report, this role for SHH is confirmed by the detection of point mutations in hereditary HPE patients2.

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References

  1. Cohen, M.M. Jr. Perspectives on holoprosencephaly: Part I. Epidemiology, genetics, and syndromology. Teratology 40, 211–235 (1989).

    Article  Google Scholar 

  2. Roessler, E. et al. Mutations in the human Sonic hedgehog gene cause holoprosencephaly. Nature Genet. 14, 357–360 (1996).

    Article  CAS  Google Scholar 

  3. Frezal, J. & Schinzel, A. Report of the committee on clinical disorders, chromosome aberrations, and uniparental disomy. Cytogenet. Cell Genet. 58, 986–1052 (1991).

    Article  Google Scholar 

  4. Gurrieri, F. et al. Physical mapping of the holoprosencephaly minimal critical region on chromosome 7q36. Nature Genet. 3, 247–251 (1993).

    Article  CAS  Google Scholar 

  5. Roessler, E. et al. Definition of a 300 kb critical region for the hoioprosencephaly 3 gene on human chromosome 7q36. Am. J. Hum. Genet. 59.S, A233 (1996).

    Google Scholar 

  6. Mackay, M. et al. Chromosomal localization in mouse and human of the vasoactive intestinal peptide receptor type 2 gene: a possible contributor to the holoprosencephaly 3 phenotype. Genomics (in the press).

  7. Muenke, M. et al. Linkage of a human brain malformation, familial holoprosencephaly, to chromosome 7 and evidence for genetic heterogeneity. Proc. Nat. Acad. Sci. U.S.A 91, 8102–8106 (1994).

    Article  CAS  Google Scholar 

  8. Belloni, E. et al. Characterization of holoprosencephaly minimal critical region in 7q36. Chromosome 7 workshop 1994. Cytogenet. Cell. Genet. 71, 31 (1995).

    Google Scholar 

  9. Bedell, M.A., Jenkins, N.A. & Copeland, N.G. Good genes in bad neighbourhoods. Nature Genet. 12, 229–232 (1996).

    Article  CAS  Google Scholar 

  10. Milot, E., Fraser, P. & Grosveld, F. Position effects and genetic disease. Trends Genet. 12, 123–126 (1996).

    Article  CAS  Google Scholar 

  11. Hatziioannou, A.G., Krauss, C.M., Lewis, M.B. & Halazonetis, T.D. Familial holoprosencephaly associated with a translocation breakpoint at chromosomal position 7q36. Am. J. Med. Gen. 40, 201–205 (1991).

    Article  CAS  Google Scholar 

  12. Krauss, C.M., Liptak, K.J., Aggarwal, A. & Robinson, D. Inheritance and phenotypic expression of a t(7;9)(q36;q34)mat. Am. J. Med. Gen. 34, 514–519 (1989).

    Article  CAS  Google Scholar 

  13. Mohler, J. & Vani, K. Molecular organization and embrionic expression of the hedgehog gene involved in cell-cell communication in segmental patterning of Drosophila. Development 115, 957–971 (1992).

    CAS  Google Scholar 

  14. Echelard, Y. et al. Sonic Hedgehog, a member of a family of putative signaling molecules, is implicated in the regulation of CNS polarity. Cell 75, 1417–1430 (1993).

    Article  CAS  Google Scholar 

  15. Riddle, R.D., Johnson, R.L., Laufer, E. & Tabin, C. Sonic hedgehog mediates the polarizing activity of the ZPA. Cell 75, 1401–1416 (1993).

    Article  CAS  Google Scholar 

  16. Johnson, R., Laufer, E., Riddle, R.D. & Tabin, C. Ectopic expression of Sonic hedgehog alters dorsal-ventral patterning of somites. Cell. 79, 1165–1173 (1994).

    Article  Google Scholar 

  17. Tanaka Hall, T.M., Porter, J., Beachy, P.A. & Leahy, D.J. A potential catalytic site revealed by the 1.7-A crystal structure of the amino-terminal signalling domain of Sonic hedgehog. Nature 378, 212–216 (1995).

    Article  Google Scholar 

  18. Chiang, C. et al. Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function. Nature 383, 407–413 (1996).

    Article  CAS  Google Scholar 

  19. Porter, J.A., Young, K.E. & Beachy, P.A. Cholesterol modification of hedgehog signaling proteins in animal development. Science 274 (1996).

    Article  CAS  Google Scholar 

  20. Tint, G.S. et al. Defective cholesterol biosynthesis associated with the Smith-Lemli-Opitz syndrome. N. Engl. J. Med. 330, 107–113 (1994).

    Article  CAS  Google Scholar 

  21. Vortkamp, A., Gessler, M. & Grzeschik, K.-H. GLI3 zinc-finger gene interrupted by translocations in Greig syndrome families. Nature 352, 539–540 (1991).

    Article  CAS  Google Scholar 

  22. Wagner, T. et al. Autosomal sex reversal and campomelic dysplasia are caused by mutations in and around the SRY-related gene SOX9. Cell 79, 1111–1120 (1994).

    Article  CAS  Google Scholar 

  23. Fantes, J. et al. Aniridia-associated cytogenetic rearrangements suggest that a position effect may cause the mutant phenotype. Hum. Mol. Genet. 4, 415–422 (1995).

    Article  CAS  Google Scholar 

  24. Scherer, S.W. et al. Physical mapping of the split hand/split foot locus on chromosome 7 and implications in syndromic ectrodactily. Hum. Mol. Genet. 3, 1345–1354 (1994).

    Article  CAS  Google Scholar 

  25. Scherer, S.W. & Tsui, L.-c. Cloning and analysis of large DNA molecules. In Advanced techniques in chromosome research (Adolph, K. ed.) 33–72 (Marcel Dekkar, New York, 1991).

    Google Scholar 

  26. Heng, H.H.Q. & Tsui, L.-C. Modes of DAPI banding and simultaneous in situ hybridization. Chromosoma 102, 325–332 (1993).

    Article  CAS  Google Scholar 

  27. Lengauer, C., Green, E.D. & Cremer, T. Fluorescence in situ hybridization of YAC clones after Alu-PCR amplification. Genomics 13, 826–828 (1992).

    Article  CAS  Google Scholar 

  28. Rommens, J.M., Mar, L., McArthur, J., Tsui, L.-C. & Scherer, S.W. In The identification of transcribed sequences. (Hochgeschwender U. & Gardiner K. eds) 65–79 (Plenum Press, New York, 1994).

    Book  Google Scholar 

  29. Rowen, L. & Koop, B.F. In Automated DNA sequencing and analysis (Adams M.D., Fields, C. & Venter, J.C., eds) (Academic Press, San Diego, 1994).

    Google Scholar 

  30. Osborne, L.R. et al. Identification of genes from a 500 kb region at 7q11.23 that is commonly deleted in Williams syndrome. Genomics 36, 328–336 (1996).

    Article  CAS  Google Scholar 

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Belloni, E., Muenke, M., Roessler, E. et al. Identification of Sonic hedgehog as a candidate gene responsible for holoprosencephaly. Nat Genet 14, 353–356 (1996). https://doi.org/10.1038/ng1196-353

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