Endocrine Abstracts

Our goal is to better understand the molecular and cellular nature of paediatric combined pituitary hormone deficiency diseases in order to facilitate improved diagnosis, treatment, and family counselling. LIM-homeodomain transcription factors regulate many aspects of development and mutations in the genes that encode these regulatory proteins are associated with several diseases. The LHX3 LIM-homeodomain protein is critical for pituitary gland organogenesis and some nervous system development. Loss of function of the LHX3 gene can cause complex paediatric syndromes involving combined pituitary hormone deficiency, limited neck rotation, hearing loss, and other symptoms. In recent studies, we have described patients with mutations in the LHX3 gene and we have investigated the aberrant mechanisms underlying loss of function of the gene or protein. Using gene knock-in technology to alter the mouse genome to mimic a human mutation in the LHX3 gene, we have generated a mouse model of paediatric combined hormone deficiency disease. This resource is allowing analyses of the developmental aspects of the disease using cellular and proteomic approaches and has also permitted studies of the influences of genetic background on the varied phenotypic outcomes of human transcription factor gene mutations. To understand the mechanism by which the human LHX3 gene is itself regulated, we have used transgenic approaches to characterise genomic promoter and enhancer elements that guide temporal and spatial expression of the gene in the endocrine and nervous systems. We are also investigating the mechanism by which LHX3 proteins interact with chromatin-associated regulatory complexes to modulate anterior pituitary gene expression. Supported by NIH HD42024 to SJR.

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 are unavailable.