{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T06:11:38Z","timestamp":1791353498685,"version":"4.3.1"},"reference-count":44,"publisher":"National Academy of Sciences","issue":"23","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2003,11,11]]},"abstract":"<jats:p>\n                    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\n                    <jats:italic>GLI2<\/jats:italic>\n                    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\n                    <jats:italic>GLI2<\/jats:italic>\n                    and human disease and highlight the role of GLI2 in human head development.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2235734100","type":"journal-article","created":{"date-parts":[[2003,11,16]],"date-time":"2003-11-16T15:42:47Z","timestamp":1068997367000},"page":"13424-13429","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":297,"title":["Loss-of-function mutations in the human\n                    <i>GLI2<\/i>\n                    gene are associated with pituitary anomalies and holoprosencephaly-like features"],"prefix":"10.1073","volume":"100","author":[{"given":"Erich","family":"Roessler","sequence":"first","affiliation":[{"name":"Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-1852; Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA 19104; Skirball Institute for Biomedical Medicine, New York University School of Medicine, New York, NY 10016; Fullerton Genetics Center, Asheville, NC 28801; Institut f\u00fcr Humangenetik Essen, Universit\u00e4tsklinikum Essen, D-45122 Essen, Germany; and Department of Genetic Medicine, Valley Children's..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang-Zhu","family":"Du","sequence":"additional","affiliation":[{"name":"Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-1852; Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA 19104; Skirball Institute for Biomedical Medicine, New York University School of Medicine, New York, NY 10016; Fullerton Genetics Center, Asheville, NC 28801; Institut f\u00fcr Humangenetik Essen, Universit\u00e4tsklinikum Essen, D-45122 Essen, Germany; and Department of Genetic Medicine, Valley Children's..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose L.","family":"Mullor","sequence":"additional","affiliation":[{"name":"Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-1852; Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA 19104; Skirball Institute for Biomedical Medicine, New York University School of Medicine, New York, NY 10016; Fullerton Genetics Center, Asheville, NC 28801; Institut f\u00fcr Humangenetik Essen, Universit\u00e4tsklinikum Essen, D-45122 Essen, Germany; and Department of Genetic Medicine, Valley Children's..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esther","family":"Casas","sequence":"additional","affiliation":[{"name":"Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-1852; Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA 19104; Skirball Institute for Biomedical Medicine, New York University School of Medicine, New York, NY 10016; Fullerton Genetics Center, Asheville, NC 28801; Institut f\u00fcr Humangenetik Essen, Universit\u00e4tsklinikum Essen, D-45122 Essen, Germany; and Department of Genetic Medicine, Valley Children's..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William P.","family":"Allen","sequence":"additional","affiliation":[{"name":"Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-1852; Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA 19104; Skirball Institute for Biomedical Medicine, New York University School of Medicine, New York, NY 10016; Fullerton Genetics Center, Asheville, NC 28801; Institut f\u00fcr Humangenetik Essen, Universit\u00e4tsklinikum Essen, D-45122 Essen, Germany; and Department of Genetic Medicine, Valley Children's..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriele","family":"Gillessen-Kaesbach","sequence":"additional","affiliation":[{"name":"Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-1852; Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA 19104; Skirball Institute for Biomedical Medicine, New York University School of Medicine, New York, NY 10016; Fullerton Genetics Center, Asheville, NC 28801; Institut f\u00fcr Humangenetik Essen, Universit\u00e4tsklinikum Essen, D-45122 Essen, Germany; and Department of Genetic Medicine, Valley Children's..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth R.","family":"Roeder","sequence":"additional","affiliation":[{"name":"Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-1852; Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA 19104; Skirball Institute for Biomedical Medicine, New York University School of Medicine, New York, NY 10016; Fullerton Genetics Center, Asheville, NC 28801; Institut f\u00fcr Humangenetik Essen, Universit\u00e4tsklinikum Essen, D-45122 Essen, Germany; and Department of Genetic Medicine, Valley Children's..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey E.","family":"Ming","sequence":"additional","affiliation":[{"name":"Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-1852; Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA 19104; Skirball Institute for Biomedical Medicine, New York University School of Medicine, New York, NY 10016; Fullerton Genetics Center, Asheville, NC 28801; Institut f\u00fcr Humangenetik Essen, Universit\u00e4tsklinikum Essen, D-45122 Essen, Germany; and Department of Genetic Medicine, Valley Children's..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ariel Ruiz i","family":"Altaba","sequence":"additional","affiliation":[{"name":"Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-1852; Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA 19104; Skirball Institute for Biomedical Medicine, New York University School of Medicine, New York, NY 10016; Fullerton Genetics Center, Asheville, NC 28801; Institut f\u00fcr Humangenetik Essen, Universit\u00e4tsklinikum Essen, D-45122 Essen, Germany; and Department of Genetic Medicine, Valley Children's..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maximilian","family":"Muenke","sequence":"additional","affiliation":[{"name":"Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-1852; 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