{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T06:12:24Z","timestamp":1791353544213,"version":"4.3.1"},"reference-count":34,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2014,12,9]],"date-time":"2014-12-09T00:00:00Z","timestamp":1418083200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100004440","name":"Wellcome Trust","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Great Ormond Street Hospital Children's Charity"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical Endocrinology"],"published-print":{"date-parts":[[2015,5]]},"abstract":"Summary<\/jats:title>Introduction<\/jats:title>The Gli family of zinc finger (GLI<\/jats:styled-content>) transcription factors mediates the sonic hedgehog signalling pathway (HH<\/jats:styled-content>) essential for CNS<\/jats:styled-content>, early pituitary and ventral forebrain development in mice. Human mutations in this pathway have been described in patients with holoprosencephaly (HPE<\/jats:styled-content>), isolated congenital hypopituitarism (CH<\/jats:styled-content>) and cranial\/midline facial abnormalities. Mutations in Sonic hedgehog<\/jats:italic> (SHH<\/jats:styled-content><\/jats:italic>) have been associated with HPE<\/jats:styled-content> but not CH<\/jats:styled-content>, despite murine studies indicating involvement in pituitary development.<\/jats:p><\/jats:sec>Objectives\/Methods<\/jats:title>We aimed to establish the role of the HH<\/jats:styled-content> pathway in the aetiology of hypothalamo\u2010pituitary disorders by screening our cohort of patients with midline defects and\/or CH<\/jats:styled-content> for mutations in SHH<\/jats:styled-content><\/jats:italic>, GLI<\/jats:styled-content>2<\/jats:italic>, Shh brain enhancer 2<\/jats:italic> (SBE<\/jats:styled-content>2<\/jats:italic>) and growth\u2010arrest specific 1<\/jats:italic> (GAS<\/jats:styled-content>1<\/jats:italic>).<\/jats:p><\/jats:sec>Results<\/jats:title>Two variants and a deletion of GLI2<\/jats:italic> were identified in three patients. A novel variant at a highly conserved residue in the zinc finger DNA\u2010binding domain, c.1552G\u00a0>\u00a0A [pE518K], was identified in a patient with growth hormone deficiency and low normal free T4. A nonsynonymous variant, c.2159G\u00a0>\u00a0A [p.R720H], was identified in a patient with a short neck, cleft palate and hypogonadotrophic hypogonadism. A 26\u00b76\u00a0Mb deletion, 2q12\u00b73\u2010q21\u00b73, encompassing GLI2<\/jats:italic> and 77 other genes, was identified in a patient with short stature and impaired growth. Human embryonic expression studies and molecular characterisation of the GLI2 mutant p.E518K support the potential pathogenicity of GLI2<\/jats:italic> mutations. No mutations were identified in GAS1<\/jats:italic> or SBE2<\/jats:italic>. A novel SHH<\/jats:italic> variant, c.1295T>A [p.I432N], was identified in two siblings with variable midline defects but normal pituitary function.<\/jats:p><\/jats:sec>Conclusions<\/jats:title>Our data suggest that mutations in SHH<\/jats:styled-content><\/jats:italic>, GAS<\/jats:styled-content>1<\/jats:italic> and SBE<\/jats:styled-content>2<\/jats:italic> are not associated with hypopituitarism, although GLI<\/jats:styled-content>2<\/jats:italic> is an important candidate for CH<\/jats:styled-content>.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cen.12637","type":"journal-article","created":{"date-parts":[[2014,10,17]],"date-time":"2014-10-17T10:21:29Z","timestamp":1413541289000},"page":"728-738","source":"Crossref","is-referenced-by-count":42,"title":["The role of the sonic hedgehog signalling pathway in patients with midline defects and congenital hypopituitarism"],"prefix":"10.1111","volume":"82","author":[{"given":"L.C.","family":"Gregory","sequence":"first","affiliation":[{"name":"Genetics and Epigenetics in Health and Disease Section Genetics and Genomic Medicine Programme UCL Institute of Child Health London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C.","family":"Gaston\u2010Massuet","sequence":"additional","affiliation":[{"name":"Centre for Endocrinology William Harvey Research Institute Barts and the London School of Medicine and Dentistry Queen Mary University of London John Vane Science Centre London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C.L.","family":"Andoniadou","sequence":"additional","affiliation":[{"name":"Craniofacial Development and Stem Cell Biology Division King College London London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G.","family":"Carreno","sequence":"additional","affiliation":[{"name":"Neural Developmental Unit UCL Institute of Child Health London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E.A.","family":"Webb","sequence":"additional","affiliation":[{"name":"Genetics and Epigenetics in Health and Disease Section Genetics and Genomic Medicine Programme UCL Institute of Child Health London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D.","family":"Kelberman","sequence":"additional","affiliation":[{"name":"Birth Defects Research Centre UCL Institute of Child Health London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.J.","family":"McCabe","sequence":"additional","affiliation":[{"name":"Genetics and Epigenetics in Health and Disease Section Genetics and Genomic Medicine Programme UCL Institute of Child Health London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L.","family":"Panagiotakopoulos","sequence":"additional","affiliation":[{"name":"Genetics and Epigenetics in Health and Disease Section Genetics and Genomic Medicine Programme UCL Institute of Child Health London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.W.","family":"Saldanha","sequence":"additional","affiliation":[{"name":"Division of Mathematical Biology National Institute for Medical Research London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H.A.","family":"Spoudeas","sequence":"additional","affiliation":[{"name":"Department of Endocrinology Great Ormond Street Hospital for Children London"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"Torpiano","sequence":"additional","affiliation":[{"name":"Department of Paediatrics Mater Dei Hospital Msida Malta"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.","family":"Rossi","sequence":"additional","affiliation":[{"name":"Department of Endocrinology The Whittington Hospital London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"Raine","sequence":"additional","affiliation":[{"name":"Department of Endocrinology The Whittington Hospital London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N.","family":"Canham","sequence":"additional","affiliation":[{"name":"North West Thames Regional Genetics Service Northwick Park Hospital Harrow UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.P.","family":"Martinez\u2010Barbera","sequence":"additional","affiliation":[{"name":"Neural Developmental Unit UCL Institute of Child Health London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.T.","family":"Dattani","sequence":"additional","affiliation":[{"name":"Genetics and Epigenetics in Health and Disease Section Genetics and Genomic Medicine Programme UCL Institute of Child Health London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2014,12,9]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.0022-202X.2004.22612.x"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.13.4.388"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.33903"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.c.30254"},{"key":"e_1_2_9_6_1","unstructured":"Solomon B.D. Gropman A.&Muenke M.(2000)Holoprosencephaly overview. GeneReviews NBK1530; PMID 20301702."},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2010.09.024"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2235734100"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1210\/er.2009-0008"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2010-1050"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2012-3224"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2013-102249"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gde.2005.04.011"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.230"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-011-1078-6"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI32032"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.33466"},{"key":"e_1_2_9_18_1","doi-asserted-by":"crossref","first-page":"3915","DOI":"10.1242\/dev.126.17.3915","article-title":"Regulation of Gli2 and Gli3 activates by an amino\u2010terminal repression domain: implication of Gli2 and Gli3 as primary mediators of Shh signalling","volume":"126","author":"Sasaki H.","year":"1999","journal-title":"Development"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2013.09.006"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1101553108"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2013.07.004"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.124.1.113"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1399-0004.2010.01606.x"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-007-0390-7"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddi222"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2011-0454"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/8.9.1683"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1530\/EJE-12-0410"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.20295"},{"key":"e_1_2_9_30_1","unstructured":"Lefkowitz J.B.(2008)Coagulation Pathway and Physiology (Chapter 1). An Algorithmic Approach to Hemostasis Testing.www.Capstaging.cap.org."},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijcard.2009.07.034"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1111\/cen.12044"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1006\/dbio.1994.1097"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/6.11.1847"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1673-8527(08)60019-3"}],"container-title":["Clinical Endocrinology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fcen.12637","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cen.12637","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,23]],"date-time":"2023-09-23T15:23:40Z","timestamp":1695482620000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/cen.12637"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,12,9]]},"references-count":34,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2015,5]]}},"alternative-id":["10.1111\/cen.12637"],"URL":"https:\/\/doi.org\/10.1111\/cen.12637","archive":["Portico"],"relation":{},"ISSN":["0300-0664","1365-2265"],"issn-type":[{"value":"0300-0664","type":"print"},{"value":"1365-2265","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,12,9]]}}}