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Combined Pituitary Hormone Deficiency Caused by Compound Heterozygosity for Two Novel Mutations in the POU Domain of the PIT1/POU1F1 Gene¹

Departments of Pediatric Endocrinology (B.I.H.-S., M.J.) and Physiological Chemistry (K.D.A.) and Center for Biomedical Genetics (K.D.A., P.C.v.d.V.), University Medical Center, 3508 AB Utrecht, The Netherlands; and Department of Pediatric Endocrinology, Emma Children’s Hospital Academic Medical Center (B.B.), 1105 AZ Amsterdam, The Netherlands

Address all correspondence and requests for reprints to: Maarten Jansen, M.D., Ph.D., Department of Pediatric Endocrinology, University Medical Center Utrecht, Room KC 03.063.0, P.O. Box 85090, 3508 AB Utrecht, The Netherlands. E-mail: m.jansen{at}wkz.azu.nl

The POU homeodomain containing transcriptional activator POU1F1, formerly called Pit1 or GHF-1, is required for the embryological determination and postnatal secretory function of the GH-, PRL-, and TSH-producing cells in the anterior pituitary. Several mutations in the gene encoding POU1F1 have been described, resulting in a syndrome of combined pituitary hormone deficiency involving these three hormones. Most of the patients with this phenotype have either a dominant negative mutation in codon 271 (R271W) or are homozygous for a recessive mutation in the POU1F1 gene; to date only one case has been reported with compound heterozygosity for two point mutations. Here, we describe a boy with severe deficiencies of GH, PRL, and TSH who had compound heterozygosity for two novel point mutations in the POU1F1 gene: a 1-bp deletion frameshift mutation (747delA), the first one described to date in this gene, which leads to a nonfunctional truncated protein lacking the entire DNA recognition helix of the POU homeodomain, and a missense mutation in the C-terminal end of the fourth -helix of the POU-specific domain (W193R),which causes a 500-fold reduction in the ability to bind to DNA and activate transcription.

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