Analysis of mouse models carrying the I26T and R160C substitutions in the transcriptional repressor HESX1 as models for septo-optic dysplasia and hypopituitarism

Ezat Sajedi, Carles Gaston-Massuet, Massimo Signore, Cynthia L Andoniadou, Daniel Kelberman, Sandra Castro, Heather C Etchevers, Dianne Gerrelli, Mehul T Dattani, Juan Pedro Martinez-Barbera

Research output: Contribution to journalArticlepeer-review

44 Citations (Scopus)

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.
Original languageEnglish
Article numberN/A
Pages (from-to)241-254
Number of pages14
JournalDisease Models & Mechanisms
Volume1
Issue number4-5
DOIs
Publication statusPublished - Nov 2008

Keywords

  • Animals
  • Body Patterning
  • Disease Models, Animal
  • Homeodomain Proteins
  • Hypopituitarism
  • Mice
  • Mutation
  • Prosencephalon
  • Repressor Proteins
  • Septo-Optic Dysplasia

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