title: Gli2 gene-environment interactions contribute to the etiological complexity of holoprosencephaly: evidence from a mouse model.
abstract: Holoprosencephaly (HPE) is a common and severe human developmental abnormality marked by malformations of the forebrain and face. Although several genetic mutations have been linked to HPE, phenotypic outcomes range dramatically, and most cases cannot be attributed to a specific cause. Gene-environment interaction has been invoked as a premise to explain the etiological complexity of HPE, but identification of interacting factors has been extremely limited. Here, we demonstrate that mutations in Gli2, which encodes a Hedgehog pathway transcription factor, can cause or predispose to HPE depending upon gene dosage. On the C57BL/6J background, homozygous GLI2 loss of function results in the characteristic brain and facial features seen in severe human HPE, including midfacial hypoplasia, hypotelorism and medial forebrain deficiency with loss of ventral neurospecification. Although normally indistinguishable from wild-type littermates, we demonstrate that mice with single-allele Gli2 mutations exhibit increased penetrance and severity of HPE in response to low-dose teratogen exposure. This genetic predisposition is associated with a Gli2 dosage-dependent attenuation of Hedgehog ligand responsiveness at the cellular level. In addition to revealing a causative role for GLI2 in HPE genesis, these studies demonstrate a mechanism by which normally silent genetic and environmental factors can interact to produce severe outcomes. Taken together, these findings provide a framework for the understanding of the extreme phenotypic variability observed in humans carrying GLI2 mutations and a paradigm for reducing the incidence of this morbid birth defect.
authors: Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI 53706, USA.
authors: Galen W
authors: GW
authors: Heyne
authors: Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI 53706, USA.|Molecular and Environmental Toxicology Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53706, USA.
authors: Joshua L
authors: JL
authors: Everson
authors: Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI 53706, USA.
authors: Lydia J
authors: LJ
authors: Ansen-Wilson
authors: Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI 53706, USA.
authors: Cal G
authors: CG
authors: Melberg
authors: Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI 53706, USA.
authors: Dustin M
authors: DM
authors: Fink
authors: Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI 53706, USA.
authors: Kia F
authors: KF
authors: Parins
authors: Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI 53706, USA.
authors: Padydeh
authors: P
authors: Doroodchi
authors: Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI 53706, USA.
authors: Caden M
authors: CM
authors: Ulschmid
authors: Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI 53706, USA rjlipinski@wisc.edu.|Molecular and Environmental Toxicology Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53706, USA.
authors: Robert J
authors: 0000-0002-1994-4090
authors: RJ
authors: Lipinski
mesh_terms: D000818:Animals; D019521:Body Patterning; D001921:Brain / Q000002:abnormalities / Q000196:embryology / Q000473:pathology; D004195:Disease Models, Animal; D005145:Face / Q000002:abnormalities / Q000196:embryology / Q000473:pathology; D005333:Fetus / Q000002:abnormalities / Q000473:pathology; D059647:Gene-Environment Interaction; D053823:Hedgehog Proteins / Q000378:metabolism; D006579:Heterozygote; D016142:Holoprosencephaly / Q000196:embryology / Q000235:genetics* / Q000473:pathology; D008024:Ligands; D000073658:Loss of Function Mutation / Q000235:genetics; D008297:Male; D008810:Mice, Inbred C57BL; D013723:Teratogens / Q000633:toxicity; D000075746:Zinc Finger Protein Gli2 / Q000235:genetics* / Q000378:metabolism
chemical_list: C000618551:Gli2 protein, mouse; D053823:Hedgehog Proteins; D008024:Ligands; C465570:Shh protein, mouse; D013723:Teratogens; D000075746:Zinc Finger Protein Gli2
keywords: Birth defects; Gene-environment; Hedgehog signaling; Holoprosencephaly