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CBP/p300-Interacting Transactivator, with Glu/Asp-Rich C-Terminal Domain, 2, and Pre-B-Cell Leukemia Transcription Factor 1 in Human Adrenal Development and Disease

Developmental Endocrinology Research Group (B.F.-d.-S., R.E.H.-D., L.L., J.C.A.) and Neural Development Unit (P.C., D.G.), University College London Institute of Child Health, University College London, London WC1N 1EH, United Kingdom; Children’s Hospital (F.M., A.H.), Technical University Dresden, 01307 Dresden, Germany; Molecular Endocrinology and Rare Diseases (D.M., Y.M.), Centre de Biologie et Pathologie Est, 69677 Bron, France; Endocrine Research (F.B.), Department of Medicine Innenstadt, University Hospital Munich, 80336 Munich, Germany

Address all correspondence and requests for reprints to: Dr. John C. Achermann, Developmental Endocrinology Research Group, Clinical & Molecular Genetics Unit, University College London Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, United Kingdom. E-mail: j.achermann{at}ich.ucl.ac.uk.

Context: Disorders of adrenal development result in significant morbidity and mortality. However, the molecular basis of human adrenal development, and many forms of disease, is still poorly understood.

Objectives: We evaluated the role of two new candidate genes, CBP/p300-interacting transactivator, with Glu/Asp-rich C-terminal domain, 2 (CITED2), and pre-B-cell leukemia transcription factor 1 (PBX1), in human adrenal development and disease.

Design: CITED2 and PBX1 expression in early human fetal adrenal development was assessed using RT-PCR and in situ hybridization. The regulation of CITED2 and PBX1 by steroidogenic factor-1 (SF-1) and dosage-sensitive sex reversal, adrenal hypoplasia congenital, critical region on the X chromosome, gene-1 (DAX1) was evaluated in NCI-H295R human adrenocortical tumor cells by studying promoter regulation. Finally, mutational analysis of CITED2 and PBX1 was performed in patients with primary adrenal disorders.

Results: CITED2 and PBX1 are expressed in the human fetal adrenal gland during early development. Both genes are activated by SF-1 in a dose-dependent manner in NCI-H295R cells, and, surprisingly, PBX1 is synergistically activated by SF-1 and DAX1. Mutational analysis failed to reveal significant coding sequence changes in individuals with primary adrenal disorders.

Conclusions: CITED2 and PBX1 are likely to be important mediators of adrenal development and function in humans, but mutations in these genes are not common causes of adrenal failure in patients in whom a molecular diagnosis remains unknown. The positive interaction between DAX1 and SF-1 in regulating PBX1 may be an important mechanism in this process.

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