{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T18:47:44Z","timestamp":1790621264167,"version":"4.1.0"},"reference-count":0,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2021,7,1]],"date-time":"2021-07-01T00:00:00Z","timestamp":1625097600000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["eje.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2021,7,1]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>The transcription factor OTX2is implicated in ocular, craniofacial, and pituitary development.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Design<\/jats:title>\n                    <jats:p>\n                      We aimed to establish the contribution of\n                      <jats:italic>OTX2<\/jats:italic>\n                      mutations in congenital hypopituitarism patients with\/without eye abnormalities, study functional consequences, and establish\n                      <jats:italic>OTX2<\/jats:italic>\n                      expression in the human brain, with a view to investigate the mechanism of action.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We screened patients from the UK (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009= 103), international centres (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009= 24), and Brazil (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009= 282); 145 were within the septo-optic dysplasia spectrum, and 264 had no eye phenotype. Transactivation ability of\n                      <jats:italic>OTX2<\/jats:italic>\n                      variants was analysed in murine hypothalamic GT1-7 neurons.\n                      <jats:italic>In situ<\/jats:italic>\n                      hybridization was performed on human embryonic brain sections. Genetically engineered mice were generated with a series of C-terminal\n                      <jats:italic>OTX2<\/jats:italic>\n                      variants.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Two chromosomal deletions and six haploinsufficient mutations were identified in individuals with eye abnormalities; an affected relative of one patient harboured the same mutation without an ocular phenotype. OTX2 truncations led to significant transactivation reduction. A missense variant was identified in another patient without eye abnormalities; however, studies revealed it was most likely not causative. In the mouse, truncations proximal to aa219 caused anophthalmia, while distal truncations and the missense variant were tolerated. During human embryogenesis,\n                      <jats:italic>OTX2<\/jats:italic>\n                      was expressed in the posterior pituitary, retina, ear, thalamus, choroid plexus, and partially in the hypothalamus, but not in the anterior pituitary.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      <jats:italic>OTX2<\/jats:italic>\n                      mutations are rarely associated with hypopituitarism in isolation without eye abnormalities, and may be variably penetrant, even within the same pedigree. Our data suggest that the endocrine phenotypes in patients with\n                      <jats:italic>OTX2<\/jats:italic>\n                      mutations are of hypothalamic origin.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1530\/eje-20-1453","type":"journal-article","created":{"date-parts":[[2021,5,5]],"date-time":"2021-05-05T13:54:11Z","timestamp":1620222851000},"page":"121-135","update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-7","source":"Crossref","is-referenced-by-count":33,"title":["The phenotypic spectrum associated with OTX2 mutations in humans"],"prefix":"10.1093","volume":"185","author":[{"given":"Louise C","family":"Gregory","sequence":"first","affiliation":[{"name":"1Section of Molecular Basis of Rare Disease, Genetics and Genomic Medicine Research & Teaching Department, UCL Great Ormond Street Institute of Child Health, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Gergics","sequence":"additional","affiliation":[{"name":"2Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marilena","family":"Nakaguma","sequence":"additional","affiliation":[{"name":"3Developmental Endocrinology Unit, Hospital das Clinicas da Faculdade de Medicina da Universidade de S\u00e3o Paulo, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hironori","family":"Bando","sequence":"additional","affiliation":[{"name":"2Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppa","family":"Patti","sequence":"additional","affiliation":[{"name":"1Section of Molecular Basis of Rare Disease, Genetics and Genomic Medicine Research & Teaching Department, UCL Great Ormond Street Institute of Child Health, London, UK"},{"name":"4Department of Pediatrics, IRCCS Istituto Giannina Gaslini"},{"name":"5Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova, Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark J","family":"McCabe","sequence":"additional","affiliation":[{"name":"1Section of Molecular Basis of Rare Disease, Genetics and Genomic Medicine Research & Teaching Department, UCL Great Ormond Street Institute of Child Health, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Fang","sequence":"additional","affiliation":[{"name":"2Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianyi","family":"Ma","sequence":"additional","affiliation":[{"name":"2Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayse Bilge","family":"Ozel","sequence":"additional","affiliation":[{"name":"2Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun Z","family":"Li","sequence":"additional","affiliation":[{"name":"2Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michele Moreira","family":"Poina","sequence":"additional","affiliation":[{"name":"3Developmental Endocrinology Unit, Hospital das Clinicas da Faculdade de Medicina da Universidade de S\u00e3o Paulo, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander A L","family":"Jorge","sequence":"additional","affiliation":[{"name":"3Developmental Endocrinology Unit, Hospital das Clinicas da Faculdade de Medicina da Universidade de S\u00e3o Paulo, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna F Figueredo","family":"Benedetti","sequence":"additional","affiliation":[{"name":"3Developmental Endocrinology Unit, Hospital das Clinicas da Faculdade de Medicina da Universidade de S\u00e3o Paulo, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio M","family":"Lerario","sequence":"additional","affiliation":[{"name":"3Developmental Endocrinology Unit, Hospital das Clinicas da Faculdade de Medicina da Universidade de S\u00e3o Paulo, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivo J P","family":"Arnhold","sequence":"additional","affiliation":[{"name":"3Developmental Endocrinology Unit, Hospital das Clinicas da Faculdade de Medicina da Universidade de S\u00e3o Paulo, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Berenice B","family":"Mendonca","sequence":"additional","affiliation":[{"name":"3Developmental Endocrinology Unit, Hospital das Clinicas da Faculdade de Medicina da Universidade de S\u00e3o Paulo, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamad","family":"Maghnie","sequence":"additional","affiliation":[{"name":"4Department of Pediatrics, IRCCS Istituto Giannina Gaslini"},{"name":"5Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova, Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sally A","family":"Camper","sequence":"additional","affiliation":[{"name":"2Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luciani R S","family":"Carvalho","sequence":"additional","affiliation":[{"name":"3Developmental Endocrinology Unit, Hospital das Clinicas da Faculdade de Medicina da Universidade de S\u00e3o Paulo, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mehul T","family":"Dattani","sequence":"additional","affiliation":[{"name":"1Section of Molecular Basis of Rare Disease, Genetics and Genomic Medicine Research & Teaching Department, UCL Great Ormond Street Institute of Child Health, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","container-title":["European Journal of 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