The phenotypic spectrum associated with OTX2 mutations in humans
| Autor: | Anna Flavia Figueredo Benedetti, Michele Moreira Poina, Mohamad Maghnie, Ivo J.P. Arnhold, Mehul T. Dattani, Hironori Bando, Mark J. McCabe, Qing Fang, Berenice B. Mendonca, Marilena Nakaguma, Alexander A. L. Jorge, Ayse Bilge Ozel, Louise C. Gregory, Antonio M. Lerario, Giuseppa Patti, Sally A. Camper, Luciani R. Carvalho, Peter Gergics, Qianyi Ma, Jun Li |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Male
Pathology Endocrinology Diabetes and Metabolism Adolescent Animals Animals Genetically Modified Brazil Cell Line Child Child Preschool Cohort Studies Female Humans Hypopituitarism Hypothalamus Infant Mice Microphthalmos Mutation Neurons Otx Transcription Factors Pedigree Pituitary Gland Septo-Optic Dysplasia United Kingdom medicine.disease_cause 0302 clinical medicine Endocrinology Missense mutation General Medicine Phenotype medicine.anatomical_structure 030220 oncology & carcinogenesis Haploinsufficiency medicine.medical_specialty 030209 endocrinology & metabolism Genetically Modified Biology 03 medical and health sciences Anterior pituitary Posterior pituitary Internal medicine medicine Preschool Anophthalmia medicine.disease eye diseases Clinical Study |
| Zdroj: | European Journal of Endocrinology |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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