A familial predisposition to Cushing’s Disease induced by a germline gain-of-function mutation of the TBX19 gene.

CCushing's Disease (CD) is a rare and insidious syndrome characterized by an unrestrained secretion of cortisol due to an ACTH-secreting pituitary adenoma. Beyond the phenotype modifications, CD is characterized by increased mortality, mainly due to the metabolic, cardiovascular, and infective complications. The pathogenesis of CD remained elusive for a long time, and only recently we have started to unveil his molecular pathways. Almost all CD occurred as a sporadic disease. In familial syndromes associated with pituitary adenomas, CD has been reported only in few subjects and always except in one case as isolated cases. Here we described a large Italian family with a surprisingly high prevalence of CD. The family includes more than 200 living subjects, 65 of them participated in the study. Among them, we found at least five cases of confirmed CD and others with various degree of abnormalities in the hypothalamic-pituitary-adrenal axis. By whole-exome and Sanger sequencing, we identified only a coding variant in heterozygosis that segregated with CD and was predicted to be pathologic. The candidate variant was a single nucleotide substitution in the TBX19 gene (c.652G>T) which was predicted to induce the change of aspartic acid to tyrosine at codon 218 of TBX19 (p. Asp218Tyr; D218Y). TBX19 is a transcription factor essential for the terminal differentiation of corticotropes and the transcription of POMC. By in vitro assays, we demonstrated that the D218Y variant increased the transcriptional activity of the POMC promoter through a stabilization of the TBX19-DNA interaction. In summary, we described the first case of familial CD induced by a germline gain-of-function mutation of the TBX19 gene.