Gregory, LC;
Gergics, P;
Nakaguma, M;
Bando, H;
Patti, G;
McCabe, MJ;
Fang, Q;
... Dattani, MT; + view all
(2021)
The phenotypic spectrum associated with OTX2 mutations in humans.
European Journal of Endocrinology
, 185
(1)
pp. 121-135.
10.1530/EJE-20-1453.
Preview |
Text
Dattani_[1479683X - European Journal of Endocrinology] The phenotypic spectrum associated with OTX2 mutations in humans.pdf Download (2MB) | Preview |
Abstract
OBJECTIVE: The transcription factor OTX2 is 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 in the human brain, with a view to investigating the mechanism of action. METHODS: We screened patients from the UK (n=103), international centers (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.
| Type: | Article |
|---|---|
| Title: | The phenotypic spectrum associated with OTX2 mutations in humans |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1530/EJE-20-1453 |
| Publisher version: | https://doi.org/10.1530/EJE-20-1453 |
| Language: | English |
| Additional information: | © 2021 The authors 2021. Original content in this article is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10127967 |
Loading...
Loading...Loading...Loading...Archive Staff Only
 |
View Item |
