Missense substitutions in the GAS1 protein present in holoprosencephaly patients reduce the affinity for its ligand,SHH |
| |
Authors: | Daniel E Pineda-Alvarez Erich Roessler Ping Hu Kshitij Srivastava Benjamin D Solomon C Evan Siple Chen-Ming Fan Maximilian Muenke |
| |
Institution: | (1) Medical Genetics Branch, National Human Genome Research Institute (NHGRI), National Institutes of Health, 35 Convent Drive, Building 35, Room 1B403, Bethesda, ML 20892-3717, USA;(2) Department of Embryology, Carnegie Institution for Science, Baltimore, ML 21218, USA; |
| |
Abstract: | 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. |
| |
Keywords: | |
本文献已被 PubMed SpringerLink 等数据库收录! |
|