Loss-of-Function Mutations in the Human GLI2 Gene Are Associated with Pituitary Anomalies and Holoprosencephaly-like Features

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 100; no. 23; pp. 13424 - 13429
• Main Authors: Roessler, Erich, Du, Yang-Zhu, Mullor, Jose L., Casas, Esther, Allen, William P., Gillessen-Kaesbach, Gabriele, Roeder, Elizabeth R., Ming, Jeffrey E., Ariel Ruiz i Altaba, Muenke, Maximilian
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 11.11.2003; National Acad Sciences
• Subjects: Alleles; Animals; Biological Sciences; COS Cells; DNA Mutational Analysis; DNA, Complementary - metabolism; Embryos; Facies; Forebrain; Genetic mutation; Genetics; GLI2 gene; holoprosencephaly; Holoprosencephaly - genetics; Humans; Hypoplasia; Kruppel-Like Transcription Factors; Messenger RNA; Mice; Mice, Inbred C3H; Models, Genetic; Mutagenesis, Site-Directed; Mutation; Nuclear Proteins; Phenotype; Phenotypes; Phylogeny; Pituitary Gland - abnormalities; Prenatal development; Prosencephalon - metabolism; Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - metabolism; Signaling; Skin Neoplasms - metabolism; Transcription Factors - genetics; Transcription Factors - metabolism; Transfection; Xenopus; Zinc Finger Protein Gli2
• DOI: 10.1073/pnas.2235734100
• ISSN: 0027-8424

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 mid-facial 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.