FAF1 Gene Involvement in Pituitary Corticotroph Tumors.

Cushing's disease (CD) is caused by rare pituitary corticotroph tumors that lead to corticotropin (ACTH) excess. Variants in , a pro-apoptotic protein involved in FAS-induced cell death, have been implicated in malignant disorders but the involvement of in pituitary tumors has not been studied. Genetic data from patients with CD were reviewed for variants in gene. Knockout mice (KO) were followed to assess the development of any pituitary disorder or cortisol excess. AtT-20 cells were used to study the effects of the variants of interest on ACTH secretion and cell proliferation. Three variants of interest were identified in 5 unique patients, two of which had rare allele frequency in genomic databases and were predicted to be likely pathogenic. KO mice were followed over time and no difference in their length/weight was noted. Additionally, KO mice did not develop any pituitary lesions and retained similar corticosterone secretion with wild type. AtT-20 cells transfected with variants of interest or WT expression plasmids showed no significant difference in cell death or Pomc gene expression. However, prediction models suggested significant differences in secondary structures of the produced proteins. In conclusion, we identified two variants in patients diagnosed with CD with a potential pathogenic effect on the protein function and structure. Our in vitro and in vivo studies did not reveal an association of defects with pituitary tumorigenesis and further studies may be needed to understand any association.