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Novel Mutations within the POU1F1 Gene Associated with Variable Combined Pituitary Hormone Deficiency

Biochemistry, Endocrinology, and Metabolism Unit and London Centre for Paediatric Endocrinology (J.P.G.T., A.M., K.S.W., M.T.D.), Institute of Child Health, London WC1N 1EH, United Kingdom; Unite Mixte de Recherche 6544 (R.R., A.S., T.B.), Centre National de la Recherche Scientifique, Universite de la Mediterranee, Institut Federatif de Recherche Jean-Roche, Faculte de Medecine Nord, 13926 Marseille, France; St. Luke’s Hospital (J.T., S.A.-M., R.P., C.V.), Department of Paediatrics, Guardamangia MSD09, Malta; National Endocrinological Research Centre (A.T.), Paediatric Unit, 117063 Moscow, Russian Federation; Division of Endocrinology (V.Z., J.H.), Hospital for Sick Children, Toronto ON M5G 1X8, Canada; Royal Manchester Children’s Hospital (P.E.C.), Pendlebury, Manchester M27 1HA, United Kingdom; Department of Endocrinology (S.S.), Christie Hospital, Wilmslow Road, Manchester M20 4BX, United Kingdom; and Royal Gwent Hospital (J.B.), Newport NP18 3XQ, United Kingdom

Address all correspondence and requests for reprints to: Dr. Mehul Dattani, Reader and Honorary Consultant in Pediatric Endocrinology, Institute of Child Health and Great Ormond Street Children’s Hospital, 30 Guilford Street, London WC1N 1EH, United Kingdom. E-mail: mdattani{at}ich.ucl.ac.uk.

Context: Mutations within the gene encoding the pituitary-specific transcription factor POU1F1 are associated with combined pituitary hormone deficiency (CPHD). Most of the affected individuals manifest GH, prolactin, and TSH deficiency.

Objective: We have now screened 129 individuals with CPHD and isolated GH deficiency for mutations within POU1F1.

Results: Causative mutations were identified in 10 of 129 individuals (7.8%). Of these, five patients harbored the dominant negative R271W mutation, which is a well-recognized mutational hot spot. We have also identified a second frequently occurring mutation, E230K, which appears to be common in Maltese patients. Additionally, we describe two novel mutations within POU1F1, an insertion of a single base pair (ins778A) and a missense mutation (R172Q). Functional studies have revealed that POU1F1 (E230K) is associated with a reduction in transactivation, although DNA-binding affinity is similar to the wild-type protein. On the other hand, POU1F1 (R172Q) is associated with a reduction in DNA binding and transactivation, whereas POU1F1 (ins778A) is associated with loss of DNA binding and a reduction in transactivation.

Conclusions: Our data suggest that the phenotype associated with POU1F1 mutations may be more variable, with the occasional preservation of TSH secretion. Additionally, our data revealed POU1F1 mutations in three patients who were diagnosed as having ACTH deficiency but who, on further evaluation, were found to have normal cortisol secretion. Hence, elucidation of the genotype led to further evaluation of the phenotype, with the cessation of cortisol replacement that had been commenced unnecessarily. These data reflect the importance of mutational analysis in patients with CPHD.

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