Human and mouseTPITgene mutations cause early onset pituitary ACTH deficiency

Abstract

Tpit is a highly cell-restricted transcription factor that is required for expression of the pro-opiomelanocortin (POMC) gene and for terminal differentiation of the pituitary corticotroph lineage. Its exclusive expression in pituitary POMC-expressing cells has suggested that its mutation may cause isolated deficiency of pituitary adrenocorticotropin (ACTH). We now show that Tpit-deficient mice constitute a model of isolated ACTH deficiency (IAD) that is very similar to human IAD patients carryingTPITgene mutations. Through genetic analysis of a panel of IAD patients, we show thatTPITgene mutations are associated at high frequency with early onset IAD, but not with juvenile forms of this deficiency. We identified seven differentTPITmutations, including nonsense, missense, point deletion, and a genomic deletion. This work defines congenital early onset IAD as a relatively homogeneous clinical entity caused by recessive transmission of loss-of-function mutations in theTPITgene.