Human and mouse TPIT gene mutations cause early onset pituitary ACTH deficiency.
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 carrying TPIT gene mutations. Through genetic analysis of a panel of IAD patients, we show that TPIT gene mutations are associated at high frequency with early onset IAD, but not with juvenile forms of this deficiency. We identified seven different TPIT mutations, 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 the TPIT gene.
Pulichino
Anne-Marie
AM
Laboratoire de Génétique moléculaire, Institut de recherches cliniques de Montréal (IRCM), Montréal, Quebec, H2W 1R7 Canada.
Vallette-Kasic
Sophie
S
Couture
Catherine
C
Gauthier
Yves
Y
Brue
Thierry
T
David
Michel
M
Malpuech
Georges
G
Deal
Cheri
C
Van Vliet
Guy
G
De Vroede
Monique
M
Riepe
Felix G
FG
Partsch
Carl-Joachim
CJ
Sippell
Wolfgang G
WG
Berberoglu
Merih
M
Atasay
Begüm
B
Drouin
Jacques
J
D000324:Adrenocorticotropic Hormone / Q000172:deficiency*; D000818:Animals; D015153:Blotting, Western; D019070:Cell Lineage; D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D005091:Exons; D017353:Gene Deletion; D005808:Genes, Recessive; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000235:genetics* / Q000502:physiology*; D006801:Humans; D051379:Mice; D008957:Models, Genetic; D008958:Models, Molecular; D009154:Mutation; D020125:Mutation, Missense; D010375:Pedigree; D010902:Pituitary Gland / Q000002:abnormalities*; D017354:Point Mutation; D020825:T-Box Domain Proteins; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology*
D018389:Codon, Nonsense; D018398:Homeodomain Proteins; D020825:T-Box Domain Proteins; C486589:TBX19 protein, human; C424031:Tbx19 protein, mouse; D014157:Transcription Factors; D000324:Adrenocorticotropic Hormone