HPE SHH variants don't undergo autoproteolytic cleavage

Stable Identifier
R-HSA-5358460
Type
Reaction [transition]
Species
Homo sapiens
Compartment
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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
16282375 Molecular mechanisms of Sonic hedgehog mutant effects in holoprosencephaly

Maity, T, Fuse, N, Beachy, PA

Proc. Natl. Acad. Sci. U.S.A. 2005
21357747 Processing and turnover of the Hedgehog protein in the endoplasmic reticulum

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

J. Cell Biol. 2011
23867461 Derlin2 protein facilitates HRD1-mediated retro-translocation of sonic hedgehog at the endoplasmic reticulum

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

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

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

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

Roessler, E, Muenke, M

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

Roessler, E, El-Jaick, KB, Dubourg, C, VĂ©lez, 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

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

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

Nat. Genet. 1996
Participants
Participant Of
Catalyst Activity
Catalyst Activity
Title
endopeptidase activity of SHH variants [endoplasmic reticulum lumen]
Physical Entity
Activity
Normal reaction
Disease
Name Identifier Synonyms
holoprosencephaly 4621 Holoprosencephaly sequence (disorder)
Authored
Reviewed
Created