Endocrine Abstracts

To better understand the molecular and cellular nature of paediatric combined pituitary hormone deficiency diseases, our laboratory has recently generated a novel mouse model of the severe paediatric diseases caused by mutations in the LHX3 transcription factor gene. Through gene targeting, we have produced an Lhx3 W227Ter mouse modeling the LHX3 W224Ter (loss of carboxyl terminus) human disease. Patients with the W224Ter mutation are of short stature and have deficiencies of GH, PRL, TSH, LH, and FSH. The homozygous Lhx3 W227Ter knock-in mice show symptoms including marked dwarfism, lethargy, reproductive problems, and pituitary hormone deficiencies. To examine the developmental time course of these deficiencies, wild-type and W227Ter knock-in mouse embryos were preserved, cryosectioned and analyzed for pituitary hormone and marker gene expression via immunohistochemistry at embryonic days 13.5, 15.5 and 17.5. Knock-in embryos had a smaller developing anterior pituitary, as well as lower expression levels of ACTH, GH, PRL, TSH, LH, α-GSU, and the pituitary transcription factor PIT1. In addition, structural defects were often noted. To examine the effects of genetic background on the disease, the W227Ter mutation was separately backcrossed six generations into the C57BL/6 and 129/Sv mouse strains. Matings of sixth generation C57BL/6 animals produced viable homozygous knock-in dwarf mice that were able to survive after weaning. By contrast, matings in the 129/Sv background have to date only produced one live knock-in pup, which died before weaning. These differences suggest that genetic background has a significant impact on LHX3-associated diseases and that the effects of modifier genes may explain the varied disease outcomes seen in human patients. Supported by NIH HD42024 to SJR and NIH F32HD068113 to KLP.

Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.

Funding: This work was supported, however funding details unavailable.