ESPE Abstracts

Hypopituitarism is genetically heterogeneous disorder that can affect solely the pituitary gland and its target organs, or it can present with craniofacial, brain, and/or neurosensory abnormalities. Mutations in over thirty genes are reported to cause hypopituitarism and growth insufficiency, yet most cases are unexplained. Mutations in the transcription factor PROP1 are the most common known cause of hypopituitarism in humans. Using Prop1 mutant mice we discovered that PROP1 regulates the transition of pituitary stem cells to hormone producing cells in an epithelial to mesenchymal-like transition process. PROP1 is necessary to maintain stem cell proliferation, migration, and pituitary placode fate identity. To discover novel causes of hypopituitarism, we carried out exome sequencing on a cohort of 26 unrelated patients with hypopituitarism and identified mutations in known genes as well as novel candidate genes. To identify additional individuals with mutations in these novel genes and candidate genes from mouse studies, we developed an efficient, cost-effective method to capture the genomic DNA from 37 candidate genes and 30 known genes. We demonstrated that the method is sensitive and accurate in identifying genetic variants and applied it to over 100 patients and their families. We identified rare, likely deleterious variants in many genes, including HESX1, POU1F1, TGIF1, SIX3, and GH1. We are using cell culture and mouse models to assess the pathogenicity of variants of unknown significance. Our findings reinforce the idea that variants in multiple genes interact to influence the severity of clinical presentation.