Loss-of-function mutations in the human GLI2 gene are associated with pituitary anomalies and holoprosencephaly-like features
- 27 October 2003
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences
- Vol. 100 (23) , 13424-13429
- https://doi.org/10.1073/pnas.2235734100
Abstract
Diminished Sonic Hedgehog (Shh) signaling is associated with the most common forebrain defect in humans, holoprosencephaly (HPE), which includes cyclopia, a phenotype also seen in mice and other vertebrates with defective Shh signaling. The secreted protein Shh acts as a crucial factor that patterns the ventral forebrain and is required for the division of the primordial eye field and brain into two discrete halves. Gli2 is one of three vertebrate transcription factors implicated as obligatory mediators of Shh signal transduction. Here, we show that loss-of-function mutations in the human GLI2 gene are associated with a distinctive phenotype (within the HPE spectrum) whose primary features include defective anterior pituitary formation and pan-hypopituitarism, with or without overt forebrain cleavage abnormalities, and HPE-like midfacial hypoplasia. We also demonstrate that these mutations lack GLI2 activity. We report on a functional association between GLI2 and human disease and highlight the role of GLI2 in human head development.Keywords
This publication has 46 references indexed in Scilit:
- Genetic analysis of zebrafishgli1andgli2reveals divergent requirements forgligenes in vertebrate developmentDevelopment, 2003
- Hedgehog–GLI signaling and the growth of the brainNature Reviews Neuroscience, 2002
- Midline and laterality defects: Left and right meet in the middle†BioEssays, 2001
- Physical and Functional Interactions between Zic and Gli ProteinsJournal of Biological Chemistry, 2001
- The Phenotypic Spectrum of GLI3 Morphopathies Includes Autosomal Dominant Preaxial Polydactyly Type-IV and Postaxial Polydactyly Type-A/B; No Phenotype Prediction from the Position of GLI3 MutationsAmerican Journal of Human Genetics, 1999
- Gli/Zic factors pattern the neural plate by defining domains of cell differentiationNature, 1998
- Mutations in the human Sonic Hedgehog gene cause holoprosencephalyNature Genetics, 1996
- Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene functionNature, 1996
- Extra-Toes (Xt) Homozygous Mutant Mice Demonstrate a Role for the Gli-3 Gene in the Development of the ForebrainCells Tissues Organs, 1994
- A mouse model of Greig cephalo–polysyndactyly syndrome: the extra–toesJ mutation contains an intragenic deletion of the Gli3 geneNature Genetics, 1993