Analysis of mouse models carrying the I26T and R160C substitutions in the transcriptional repressor HESX1 as models for septo-optic dysplasia and hypopituitarism
| Autor: | Juan Pedro Martinez-Barbera, Carles Gaston-Massuet, Massimo Signore, Sandra B.R. Castro, Heather C. Etchevers, Dianne Gerrelli, Ezat Sajedi, Mehul T. Dattani, Daniel Kelberman, Cynthia L. Andoniadou |
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| Rok vydání: | 2008 |
| Předmět: |
medicine.medical_specialty
Mutant Neuroscience (miscellaneous) Medicine (miscellaneous) Repressor Locus (genetics) Hypopituitarism Biology General Biochemistry Genetics and Molecular Biology Mice Prosencephalon Septo-Optic Dysplasia Immunology and Microbiology (miscellaneous) Internal medicine medicine Animals Body Patterning Homeodomain Proteins Optic nerve hypoplasia Septo-optic dysplasia medicine.disease Null allele Molecular biology Repressor Proteins Disease Models Animal Endocrinology Mutation Forebrain Research Article |
| Zdroj: | Disease Models & Mechanisms. 1:241-254 |
| ISSN: | 1754-8411 1754-8403 |
| DOI: | 10.1242/dmm.000711 |
| Popis: | SUMMARY A homozygous substitution of the highly conserved isoleucine at position 26 by threonine (I26T) in the transcriptional repressor HESX1 has been associated with anterior pituitary hypoplasia in a human patient, with no forebrain or eye defects. Two individuals carrying a homozygous substitution of the conserved arginine at position 160 by cysteine (R160C) manifest septo-optic dysplasia (SOD), a condition characterised by pituitary abnormalities associated with midline telencephalic structure defects and optic nerve hypoplasia. We have generated two knock-in mouse models containing either the I26T or R160C substitution in the genomic locus. Hesx1I26T/I26T embryos show pituitary defects comparable with Hesx1−/− mouse mutants, with frequent occurrence of ocular abnormalities, although the telencephalon develops normally. Hesx1R160C/R160C mutants display forebrain and pituitary defects that are identical to those observed in Hesx1−/− null mice. We also show that the expression pattern of HESX1 during early human development is very similar to that described in the mouse, suggesting that the function of HESX1 is conserved between the two species. Together, these results suggest that the I26T mutation yields a hypomorphic allele, whereas R160C produces a null allele and, consequently, a more severe phenotype in both mice and humans. |
| Databáze: | OpenAIRE |
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