Hh mutants abrogate ligand secretion

Stable Identifier
Homo sapiens
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Hh signaling is required for a number of developmental processes, and mutations that disrupt the normal processing and biogenesis of Hh ligand can result in neonatal abnormalities. SHH is one of a number of genes that have been associated with the congenital disorder holoprosencephaly, which causes abnormalities in brain and craniofacial development (Roessler et al, 2009; reviewed in Roessler and Muenke, 2011). SHH variants associated with the condition affect the autocatalytic processing of the precursor and dramatically impair the production of the secreted active Hh-Np, abrogating signaling (reviewed in Pan et al, 2013). Aberrant Hh signaling is also associated with gondal dysgenesis syndromes in which palmitoylation of DHH is abrogated by mutation of the acyltransferase HHAT (Callier et al, 2014).
Literature References
PubMed ID Title Journal Year
24784881 Loss of Function Mutation in the Palmitoyl-Transferase HHAT Leads to Syndromic 46,XY Disorder of Sex Development by Impeding Hedgehog Protein Palmitoylation and Signaling

Rolland, A, Bernard, P, Callier, P, Antonarakis, SE, Nef, S, Faivre, L, Resh, MD, Desdoits-Lethimonier, C, Stévant, I, Borel, C, Conne, B, Thauvin-Robinet, C, Calvel, P, Santoni, F, Kuhne, F, Wilhelm, D, Mugneret, F, Kurosaka, H, Jaruzelska, J, Jégou, B, Vannier, A, Trainor, PA, Guipponi, M, Huet, F, Mazaud-Guittot, S, Matevossian, A, Makrythanasis, P, Lambert, S, Zimmermann, C

PLoS Genet. 2014
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, Vélez, JI, Dubourg, C, Ouspenskaia, M, El-Jaick, KB, Lacbawan, F, Paulussen, A, Smeets, HJ, Solomon, BD, Muenke, M

Hum. Mutat. 2009
23565096 A review of hedgehog signaling in cranial bone development

James, AW, Chang, L, Pan, A, Nguyen, A

Front Physiol 2013
Name Identifier Synonyms
holoprosencephaly DOID:4621 Holoprosencephaly sequence (disorder)
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