Missense substitutions in the GAS1 protein present in holoprosencephaly patients reduce the affinity for its ligand, SHH

Hum Genet. 2012 Feb;131(2):301-10. doi: 10.1007/s00439-011-1078-6. Epub 2011 Aug 13.


Holprosencephaly (HPE) is the most common disorder of the developing forebrain in humans, and is characterized by varying degrees of abnormal union of the cerebral hemispheres. These defects are typically co-associated with midline craniofacial anomalies. The combination of forebrain and craniofacial defects that comprise HPE can present along a broad and variable phenotypic spectrum. Both the SHH and NODAL signaling pathways play important roles in the pathogenesis of this disorder. Disruption of these pathways by chromosomal rearrangements, mutations in pathway-related genes and/or biochemical alterations are proposed to contribute to HPE in a large number of patients. Additional factors that are not yet fully delineated are also very likely to be involved in the pathogenesis and phenotypic heterogeneity of the disorder. Genetic loss of GAS1, a cell membrane receptor and positive regulator of SHH, has been demonstrated to contribute to the HPE phenotypic spectrum in animal models. We have evaluated the coding and flanking sequence of GAS1 in 394 patients who have clinical findings within the HPE phenotypic spectrum, and now report five novel missense sequence variants among five unrelated HPE probands. Finally, we tested the effect of these variants (as well as previously reported GAS1 variants) on the ability of GAS1 to bind to SHH. Here, we demonstrate that sequence variants in GAS1 can impair its physical interaction with SHH, suggesting a decrease in the SHH downstream signaling cascade as a pathogenic mechanism of disease.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Sequence
  • Cell Cycle Proteins / genetics*
  • Cell Cycle Proteins / metabolism
  • GPI-Linked Proteins / genetics
  • GPI-Linked Proteins / metabolism
  • Hedgehog Proteins / metabolism
  • Holoprosencephaly / genetics*
  • Humans
  • Ligands
  • Molecular Sequence Data
  • Mutation, Missense*
  • Sequence Analysis, DNA


  • Cell Cycle Proteins
  • GAS1 protein, human
  • GPI-Linked Proteins
  • Hedgehog Proteins
  • Ligands
  • SHH protein, human