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Couture C.,Institute Of Recherches Cliniques Of Montreal | Saveanu A.,Laboratoire Center National Of La Recherche Scientifique Unite Mixte Of Recherche 6231 | Saveanu A.,Center Hospitalier University Conception | Barlier A.,Laboratoire Center National Of La Recherche Scientifique Unite Mixte Of Recherche 6231 | And 13 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2012

Context: Congenital isolated ACTH deficiency (IAD) is a rare disease characterized by low plasma ACTHandcortisol levelsandpreservation of all other pituitary hormones. This conditionwaspoorly defined beforeweidentified TPIT, a T-box transcription factor with a specific role in differentiation of the corticotroph lineage in mice and humans, as its principal molecular cause. Objective: We have enlarged our series of IAD patients to better characterize the phenotype and the genotype of this rare disease. Design: Each exon of the TPIT gene was amplified and sequenced in IAD patients without any identified cause. A functional analysis of each new TPIT mutation was performed. Results: We described the largest series of 91 IAD patients and identified three distinct groups: neonatal onset complete or partial IAD or late onset IAD. We did not identify any TPIT mutation in patients with partial or late-onset IAD. However, we found a TPIT mutation in 65% of patients with neonatal-onset complete IAD. These patients arehomozygousorcompoundheterozygous for TPIT mutations, and their parents are healthy heterozygous carriers. We identified nine new mutations: four missense, one one-nucleotide deletion, three splice-site mutations, and one large deletion. TPIT mutations lead to loss of function by different mechanisms, such as non-sensemediated mRNA decay, abnormal mRNA splicing, loss of TPIT DNA binding or protein-protein interaction defects. Conclusion: TPIT mutations are responsible for two thirds of neonatal-onset complete IAD but can not be detected in partial or late-onset IAD. Copyright © 2012 by The Endocrine Society. Source

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