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Gli2 gene-environment interactions contribute to the etiological complexity of holoprosencephaly: evidence from a mouse model.
- Source :
-
Disease models & mechanisms [Dis Model Mech] 2016 Nov 01; Vol. 9 (11), pp. 1307-1315. Date of Electronic Publication: 2016 Sep 01. - Publication Year :
- 2016
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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.<br />Competing Interests: The authors declare no competing or financial interests.<br /> (© 2016. Published by The Company of Biologists Ltd.)
- Subjects :
- Animals
Body Patterning
Brain abnormalities
Brain embryology
Brain pathology
Disease Models, Animal
Face abnormalities
Face embryology
Face pathology
Fetus abnormalities
Fetus pathology
Hedgehog Proteins metabolism
Heterozygote
Holoprosencephaly embryology
Holoprosencephaly pathology
Ligands
Loss of Function Mutation genetics
Male
Mice, Inbred C57BL
Teratogens toxicity
Zinc Finger Protein Gli2 metabolism
Gene-Environment Interaction
Holoprosencephaly genetics
Zinc Finger Protein Gli2 genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1754-8411
- Volume :
- 9
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Disease models & mechanisms
- Publication Type :
- Academic Journal
- Accession number :
- 27585885
- Full Text :
- https://doi.org/10.1242/dmm.026328