HPE SHH variants don't undergo autoproteolytic cleavage

Stable Identifier
Reaction [transition]
Homo sapiens
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Holoprosencephaly (HPE) is a congenital brain disorder that results in abnormal formation and septation of the central nervous system during development. Genetic studies have implicated more than 10 chromosomal locations in the development of HPE, and 7 contributing genes, including SHH have been identified (Belloni et al, 1996; reviewed in Roessler and Muenke, 2011). Missense and truncation mutations in SHH that impair Hh signaling have been identified in cases of HPE. Many of the mutations cluster in regions of the protein that contribute to the autoproteolytic cleavage of the precursor. Because this processing is required for the production of Hh-Np (the active signaling molecule), Hh-processing mutants abolish Hh ligand secretion and Hh signaling. Mutations of residues in the conserved G-C-F motif containing the catalytic cysteine, and of residues in the sterol recognition region (SRR) in the C-terminus of Hh have been identified in HPE and abrogate ligand secretion and signaling and are thought to disrupt the cleavage reaction in the ER (Roessler et al, 2009; Traiffort et al, 2004; Maity et al, 2005; Chen et al, 2011; Huang et al, 2013).
Literature References
PubMed ID Title Journal Year
21357747 Processing and turnover of the Hedgehog protein in the endoplasmic reticulum

Jao, C, Rapoport, TA, Tang, HY, Chu, YR, Schulman, S, Huang, CH, Chen, X, Salic, A, Mueller, B, Tukachinsky, H

J. Cell Biol. 2011
16282375 Molecular mechanisms of Sonic hedgehog mutant effects in holoprosencephaly

Beachy, PA, Fuse, N, Maity, T

Proc. Natl. Acad. Sci. U.S.A. 2005
23867461 Derlin2 protein facilitates HRD1-mediated retro-translocation of sonic hedgehog at the endoplasmic reticulum

Ye, Y, Chu, YR, Hsiao, HT, Huang, CH, Chen, X

J. Biol. Chem. 2013
15292211 Functional characterization of sonic hedgehog mutations associated with holoprosencephaly

David, V, Traiffort, E, Odent, S, Faure, H, Durou, MR, Rognan, D, Dubourg, C, Ruat, M

J. Biol. Chem. 2004
20104595 The molecular genetics of holoprosencephaly

Muenke, M, Roessler, E

Am J Med Genet C Semin Med Genet 2010
19603532 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

Pineda-Alvarez, DE, Hehr, U, Bale, S, Zhou, N, Odent, S, Roessler, E, David, V, Bendavid, C, VĂ©lez, JI, Dubourg, C, Ouspenskaia, M, El-Jaick, KB, Lacbawan, F, Paulussen, A, Smeets, HJ, Solomon, BD, Muenke, M

Hum. Mutat. 2009
8896571 Identification of Sonic hedgehog as a candidate gene responsible for holoprosencephaly

Donis-Keller, H, Frumkin, A, Martindale, D, Belloni, E, Tsui, LC, Heng, HH, Siegel-Bartelt, J, Scherer, SW, Traverso, G, Muenke, M, Roessler, E, Koop, B, Mitchell, HF, Helms, C, Rommens, JM, Hing, AV

Nat. Genet. 1996
Catalyst Activity

endopeptidase activity of SHH variants [endoplasmic reticulum lumen]

Normal reaction
Functional status

Loss of function of SHH variants [endoplasmic reticulum lumen]

Name Identifier Synonyms
holoprosencephaly DOID:4621 Holoprosencephaly sequence (disorder)
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