The phenotypic spectrum associated with OTX2 mutations in humans

Objective The transcription factor OTX2is implicated in ocular, craniofacial, and pituitary development. Design We aimed to establish the contribution of OTX2 mutations in congenital hypopituitarism patients with/without eye abnormalities, study functional consequences, and establish OTX2 expression...

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Published in:	European journal of endocrinology Vol. 185; no. 1; pp. 121 - 135
Main Authors:	Gregory, Louise C, Gergics, Peter, Nakaguma, Marilena, Bando, Hironori, Patti, Giuseppa, McCabe, Mark J, Fang, Qing, Ma, Qianyi, Ozel, Ayse Bilge, Li, Jun Z, Poina, Michele Moreira, Jorge, Alexander A L, Benedetti, Anna F Figueredo, Lerario, Antonio M, Arnhold, Ivo J P, Mendonca, Berenice B, Maghnie, Mohamad, Camper, Sally A, Carvalho, Luciani R S, Dattani, Mehul T
Format:	Journal Article
Language:	English
Published:	England Bioscientifica Ltd 25-05-2021 Oxford University Press
Subjects:	Adolescent Animals Animals, Genetically Modified Anophthalmia Brazil Cell Line Child Child, Preschool Choroid plexus Clinical Study Cohort Studies Craniofacial growth Dysplasia Embryogenesis Eye Female Genetic engineering Humans Hybridization Hypopituitarism Hypopituitarism - embryology Hypopituitarism - genetics Hypopituitarism - physiopathology Hypothalamus Hypothalamus - cytology Infant Male Mice Microphthalmos - embryology Microphthalmos - genetics Microphthalmos - physiopathology Mutation Neurons - pathology Neurons - physiology Otx Transcription Factors - genetics Otx2 protein Patients Pedigree Phenotypes Pituitary (anterior) Pituitary (posterior) Pituitary Gland - embryology Pituitary Gland - pathology Pituitary Gland - physiopathology Retina Septo-optic dysplasia Septo-Optic Dysplasia - embryology Septo-Optic Dysplasia - genetics Septo-Optic Dysplasia - physiopathology Thalamus United Kingdom Brazil United Kingdom
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Summary:	Objective The transcription factor OTX2is implicated in ocular, craniofacial, and pituitary development. Design We aimed to establish the contribution of OTX2 mutations in congenital hypopituitarism patients with/without eye abnormalities, study functional consequences, and establish OTX2 expression in the human brain, with a view to investigate the mechanism of action. Methods We screened patients from the UK (n = 103), international centres (n = 24), and Brazil (n = 282); 145 were within the septo-optic dysplasia spectrum, and 264 had no eye phenotype. Transactivation ability of OTX2 variants was analysed in murine hypothalamic GT1-7 neurons. In situ hybridization was performed on human embryonic brain sections. Genetically engineered mice were generated with a series of C-terminal OTX2 variants. Results 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, OTX2 was expressed in the posterior pituitary, retina, ear, thalamus, choroid plexus, and partially in the hypothalamus, but not in the anterior pituitary. Conclusions OTX2 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 OTX2 mutations are of hypothalamic origin.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 L C Gregory, P Gergics and M Nakaguma contributed equally to this work
ISSN:	0804-4643 1479-683X
DOI:	10.1530/EJE-20-1453