{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T03:29:55Z","timestamp":1780630195299,"version":"3.54.1"},"reference-count":26,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2019,1,7]],"date-time":"2019-01-07T00:00:00Z","timestamp":1546819200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Endocrinology"],"published-print":{"date-parts":[[2019,3]]},"abstract":"<jats:title>Summary<\/jats:title><jats:sec><jats:title>Context<\/jats:title><jats:p>The Gli\u2010family of zinc\u2010finger transcription factors regulates the Sonic Hedgehog (Shh) signalling pathway that plays a key role in early pituitary and ventral forebrain development. Heterozygous <jats:italic>GLI2<\/jats:italic> loss of function mutations in humans have been reported in holoprosencephaly (HPE), HPE\u2010like phenotypes associated with pituitary anomalies and combined pituitary hormone deficiency with or without other extra\u2010pituitary findings.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>The aim of this study was the search for <jats:italic>GLI2<\/jats:italic> mutations in a cohort of Italian CPHD patients and the assessment of a pathogenic role for the identified variants through in vitro studies.<\/jats:p><\/jats:sec><jats:sec><jats:title>Patients<\/jats:title><jats:p>One hundred forty\u2010five unrelated CPHD patients diagnosed with or without extra\u2010pituitary manifestations were recruited from different Italian centres.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The <jats:italic>GLI2<\/jats:italic> mutation screening was carried out through direct sequencing of all the 13 exons and intron\u2010exon boundaries. Luciferase reporter assays were performed to evaluate the role of the detected missense variants.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Five different novel heterozygous non\u2010synonymous <jats:italic>GLI2<\/jats:italic> variants were identified in five patients. The mutations were three missense (p.Pro386Leu, p.Tyr575His, p.Ala593Val), one frameshift (p.Val1111Glyfs*19) and one nonsense (p.Arg1226X). The latter two mutants are likely pathogenic since they lead to a truncated protein. The in vitro functional study of the plasmids bearing two of the three missense variants (namely p.Tyr575His and p.Ala593Val) revealed a significant reduction in transcriptional activity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>In conclusion, the analysis of <jats:italic>GLI2<\/jats:italic> in individuals with CPHD led to the identification of five variations with a likely negative impact on the GLI2 protein, confirming that <jats:italic>GLI2<\/jats:italic> is an important causative gene in CPHD. The functional in vitro study analysis performed on the missense variations were useful to strengthen the hypothesis of pathogenicity.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cen.13914","type":"journal-article","created":{"date-parts":[[2018,12,13]],"date-time":"2018-12-13T06:39:13Z","timestamp":1544683153000},"page":"449-456","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Novel <i>GLI2<\/i> mutations identified in patients with Combined Pituitary Hormone Deficiency (CPHD): Evidence for a pathogenic effect by functional characterization"],"prefix":"10.1111","volume":"90","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0301-9295","authenticated-orcid":false,"given":"Deepak","family":"Babu","sequence":"first","affiliation":[{"name":"Laboratory of Genetics, Department of Health Sciences University of Eastern Piedmont Novara Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonella","family":"Fanelli","sequence":"additional","affiliation":[{"name":"Laboratory of Genetics, Department of Health Sciences University of Eastern Piedmont Novara Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simona","family":"Mellone","sequence":"additional","affiliation":[{"name":"Laboratory of Genetics, Department of Health Sciences University of Eastern Piedmont Novara Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ranjith","family":"Muniswamy","sequence":"additional","affiliation":[{"name":"Laboratory of Genetics, Department of Health Sciences University of Eastern Piedmont Novara Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malgorzata","family":"Wasniewska","sequence":"additional","affiliation":[{"name":"Dipartimento di Patologia Umana dell'adulto e dell'et\u00e0 evolutiva \"Gaetano Barresi\" Universit\u00e0 degli Studi di Messina Messina Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9660-5335","authenticated-orcid":false,"given":"Flavia","family":"Prodam","sequence":"additional","affiliation":[{"name":"Unit of Pediatrics, Department of Health Sciences University of Eastern Piedmont Novara Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonella","family":"Petri","sequence":"additional","affiliation":[{"name":"Unit of Pediatrics, Department of Health Sciences University of Eastern Piedmont Novara Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simonetta","family":"Bellone","sequence":"additional","affiliation":[{"name":"Unit of Pediatrics, Department of Health Sciences University of Eastern Piedmont Novara Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Carolina","family":"Salerno","sequence":"additional","affiliation":[{"name":"Pediatric Endocrine Unit, Department of Translational Medical Sciences University of Naples Federico II Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mara","family":"Giordano","sequence":"additional","affiliation":[{"name":"Laboratory of Genetics, Department of Health Sciences University of Eastern Piedmont Novara 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