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      Central Hypothyroidism Reveals Compound Heterozygous Mutations in the Pit-1 Gene

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          Mutations in the gene encoding the Pit-1 transcriptional activator interfere with the embryologic determination and ultimate functions of anterior pituitary cells that produce growth hormone (GH), prolactin (Prl) and thyroid-stimulating hormone (TSH). Central hypothyroidism is often the presenting feature of combined pituitary hormone deficiency (CPHD), but it is not detected in screening programs that rely upon elevation of TSH. We report a child whose hypothyroidism was recognized clinically at age 6 weeks, and subsequently found to have GH and Prl as well as TSH deficiency. With thyroxine and GH replacement he has reached the 70th percentile for height and has normal intelligence. Molecular analysis of genomic DNA for Pit-1 revealed the presence of compound heterozygous recessive mutations: a nonsense mutation in codon 172 and a novel missense mutation substituting glycine for glutamate at codon 174. This case is the first demonstration of CPHD due to compound heterozygous Pit-1 point mutations, as most reported cases of the CPHD phenotype involve either the dominant negative R271W allele or homozygosity for recessive Pit-1 mutations. Therefore, in cases of CPHD, the possibilities of compound heterozygosity for two different Pit-1 mutations, or homozygosity for mutations in the epigenetic gene, Prop-1, should be considered.

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          Most cited references 4

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          Dwarf locus mutants lacking three pituitary cell types result from mutations in the POU-domain gene pit-1.

          Mutations at the mouse dwarf locus (dw) interrupt the normal development of the anterior pituitary gland, resulting in the loss of expression of growth hormone, prolactin and thyroid-stimulating hormone, and hypoplasia of their respective cell types. Disruptions in the gene encoding the POU-domain transcription factor, Pit-1, occur in both characterized alleles of the dwarf locus. The data indicate that Pit-1 is necessary for the specification of the phenotype of three cell types in the anterior pituitary, and directly link a transcription factor to commitment and progression events in mammalian organogenesis.
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            Pituitary lineage determination by the Prophet of Pit-1 homeodomain factor defective in Ames dwarfism.

            The gene apparently responsible for a heritable form of murine pituitary-dependent dwarfism (Ames dwarf, df) has been positionally cloned, identifying a novel, tissue-specific, paired-like homeodomain transcription factor, termed Prophet of Pit-1 (Prop-1). The df phenotype results from an apparent failure of initial determination of the Pit-1 lineage required for production of growth hormone, prolactin or thyroid-stimulating hormone, resulting in dysmorphogenesis and failure to activate Pit-1 gene expression. These results imply that a cascade of tissue-specific regulators is responsible for the determination and differentiation of specific cell lineages in pituitary organogenesis.
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              The POU-specific domain of Pit-1 is essential for sequence-specific, high affinity DNA binding and DNA-dependent Pit-1-Pit-1 interactions.

              Pit-1 is a member of a family of transcription factors sharing two regions of homology: a highly conserved POU-specific (POUS) domain and a more divergent homeodomain (POUHD). Analysis of mutant Pit-1 proteins suggests that, while the POUHD is required and sufficient for low affinity DNA binding, the POUS domain is necessary for high affinity binding and accurate recognition of natural Pit-1 response elements. Pit-1 is monomeric in solution but associates as a dimer on its DNA response element, exhibiting DNA-dependent protein-protein interactions requiring the POUS domain. Analysis of alpha-helical domains and conserved structures in Pit-1 suggests that POU domain proteins interact with their DNA recognition sites differently than classic homeodomain proteins, with both the POUHD and the POUS domain contacting DNA. Transcriptional activity of Pit-1 on enhancer elements is conferred primarily by a Ser- and Thr-rich N-terminal region unrelated to other known transcription-activating motifs.

                Author and article information

                Horm Res Paediatr
                Hormone Research in Paediatrics
                S. Karger AG
                February 1998
                14 January 1998
                : 49
                : 2
                : 98-102
                a Division of Pediatric Endocrinology, Department of Pediatrics, Emory University School of Medicine, Atlanta, Ga.; b Department of Pediatrics, University of Chicago, Ill.; c Department of Cell and Molecular Biology, and d Molecular and Cellular Biology Graduate Program, Tulane University, New Orleans, La., USA
                23134 Horm Res 1998;49:98–102
                © 1998 S. Karger AG, Basel

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                Figures: 2, Tables: 1, References: 15, Pages: 5
                Case Report


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