Clinical issue
The pituitary gland is regulated by the hypothalamus in the brain and is essential for controlling growth, reproduction, and stress responses. Developmental pituitary defects lead to hypopituitarism, which can range from loss of a single pituitary hormone to loss of multiple or all pituitary hormones. Isolated growth hormone deficiency (IGHD) is most common, affecting one in as many as 4000 people. Combined pituitary hormone deficiency (CPHD), characterised by deficiency of multiple pituitary hormones, is less common than IGHD, and is associated with considerable morbidity and mortality. Septo-optic dysplasia (SOD; also referred to as de Morsier syndrome) is associated with anterior brain and eye defects, and may involve the gene for HESX1. HESX1 is a transcription factor required for normal development of the forebrain and pituitary gland in both humans and mice. Mutation of HESX1 is associated with hypopituitarism, although, the wide range of phenotypes manifested in these diseases makes it difficult to determine the influence of these mutations.
Results
Here, HESX1 expression was identified in the anterior brain and pituitary gland of mice and humans, establishing the mouse as a physiologically relevant model for understanding HESX1 mutations associated with human disease. Mouse mutants were created harbouring two common point mutations found in human hypopituitarism, which displayed a hierarchy of defects. Hesx1 function had the greatest influence in the pituitary gland, medium effects on eye precursors and mild effects in the anterior brain (the location of the developing hypothalamus). In addition, the two mutations examined caused distinct phenotypes. An R160C substitution produced a non-functional protein that was lethal, whereas I26T had reduced functionality and a milder phenotype. This study shows very different effects of two knock-in mutations of Hesx1. Although eye defects were noted in both mutants, only the R160C substitution proved lethal, suggesting that the neural control of pituitary function may be impaired in these mutants.
Implications and future directions
This study advances our understanding of the contributions of HESX1 to complex and variable manifestations of human hypopituitarism. Consistent with these findings, pituitary dysfunction is most common in patients with HESX1 mutations, followed by eye defects and then anterior brain abnormalities. This work also demonstrates unique consequences of R160C versus I26T mutations in HESX1, which are commonly associated with human disease.
