title: Analysis of mouse models carrying the I26T and R160C substitutions in the transcriptional repressor HESX1 as models for septo-optic dysplasia and hypopituitarism.
abstract: 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. Hesx1(I26T/I26T) embryos show pituitary defects comparable with Hesx1(-/-) mouse mutants, with frequent occurrence of ocular abnormalities, although the telencephalon develops normally. Hesx1(R160C/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.
authors.affiliation: Neural Development Unit, Institute of Child Health, University College London, London, UK.
authors.forename: Ezat
authors.initials: E
authors.lastname: Sajedi
authors.forename: Carles
authors.initials: C
authors.lastname: Gaston-Massuet
authors.forename: Massimo
authors.initials: M
authors.lastname: Signore
authors.forename: Cynthia L
authors.initials: CL
authors.lastname: Andoniadou
authors.forename: Daniel
authors.initials: D
authors.lastname: Kelberman
authors.forename: Sandra
authors.initials: S
authors.lastname: Castro
authors.forename: Heather C
authors.initials: HC
authors.lastname: Etchevers
authors.forename: Dianne
authors.initials: D
authors.lastname: Gerrelli
authors.forename: Mehul T
authors.initials: MT
authors.lastname: Dattani
authors.forename: Juan Pedro
authors.initials: JP
authors.lastname: Martinez-Barbera
mesh_terms: D000818:Animals; D019521:Body Patterning; D004195:Disease Models, Animal; D018398:Homeodomain Proteins / Q000235:genetics*; D007018:Hypopituitarism / Q000235:genetics*; D051379:Mice; D009154:Mutation; D016548:Prosencephalon / Q000002:abnormalities / Q000196:embryology; D012097:Repressor Proteins / Q000235:genetics*; D025962:Septo-Optic Dysplasia / Q000235:genetics*
chemical_list: C489736:HESX1 protein, human; D018398:Homeodomain Proteins; D012097:Repressor Proteins