Molecular mechanisms of Sonic hedgehog mutant effects in holoprosencephaly

Tapan Maity, Naoyuki Fuse, Philip A. Beachy

Research output: Contribution to journalArticle

71 Citations (Scopus)

Abstract

Holoprosencephaly (HPE), a human developmental brain defect, usually is also associated with varying degrees of midline facial dysmorphism. Heterozygous mutations in the Sonic hedgehog (SHH) gene are the most common genetic lesions associated with HPE, and loss of Shh function in the mouse produces cyclopia and alobar forebrain development. The N-terminal domain (ShhNp) of Sonic hedgehog protein, generated by cholesterol-dependent autoprocessing and modification at the C terminus and by palmitate addition at the N terminus, is the active ligand in the Shh signal transduction pathway. Here, we analyze seven reported missense mutations (G31R, D88V, Q100H, N115K, W117G, W117R, and E188Q) that alter the N-terminal signaling domain of Shh protein, and show that two of these mutations (Q100H and E188Q), which are questionably linked to HPE, produce no detectable effects on function. The remaining five alterations affect normal processing, Ptc binding, and signaling to varying degrees. These effects include introduction of a recognition site for furin-like proteases by the G31R alteration, resulting in cleavage of 11 amino acid residues from the N terminus of ShhNp and consequent reduced signaling potency. Two other alterations, W117G and W117R, cause temperature-dependent misfolding and retention in the sterol-poor endoplasmic reticulum, thus disrupting cholesterol-dependent autoprocessing.

Original languageEnglish
Pages (from-to)17026-17031
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number47
DOIs
Publication statusPublished - 2005 Nov 22
Externally publishedYes

Keywords

  • Autoprocessing
  • Development protein misfolding
  • Endoplasmic reticulum retention

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'Molecular mechanisms of Sonic hedgehog mutant effects in holoprosencephaly'. Together they form a unique fingerprint.

  • Cite this