Meta-Biol

• Pathways

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).