Novel mutations within the POU1F1 gene associated with variable combined pituitary hormone deficiency. 2005

James P G Turton, and Rachel Reynaud, and Ameeta Mehta, and John Torpiano, and Alexandru Saveanu, and Kathryn S Woods, and Anatoly Tiulpakov, and Vera Zdravkovic, and Jill Hamilton, and Simon Attard-Montalto, and Ray Parascandalo, and Cecil Vella, and Peter E Clayton, and Stephen Shalet, and John Barton, and Thierry Brue, and Mehul T Dattani
Biochemistry, Endocrinology, and Metabolism Unit and London Centre for Paediatric Endocrinology, Institute of Child Health, London, United Kingdom.

BACKGROUND 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.

UI MeSH Term Description Entries
D007018 Hypopituitarism Diminution or cessation of secretion of one or more hormones from the anterior pituitary gland (including LH; FOLLICLE STIMULATING HORMONE; SOMATOTROPIN; and CORTICOTROPIN). This may result from surgical or radiation ablation, non-secretory PITUITARY NEOPLASMS, metastatic tumors, infarction, PITUITARY APOPLEXY, infiltrative or granulomatous processes, and other conditions. Adenohypophyseal Hyposecretion,Anterior Pituitary Hyposecretion Syndrome,Sheehan Syndrome,Simmonds Disease,Hyposecretion Syndrome, Anterior Pituitary,Hyposecretion, Adenohypophyseal,Pituitary Insufficiency,Postpartum Hypopituitarism,Postpartum Panhypopituitarism,Postpartum Pituitary Insufficiency,Sheehan's Syndrome,Simmonds' Disease,Disease, Simmonds,Hypopituitarism, Postpartum,Insufficiency, Pituitary,Panhypopituitarism, Postpartum,Pituitary Insufficiency, Postpartum,Sheehans Syndrome,Simmond's Disease,Syndrome, Sheehan,Syndrome, Sheehan's
D008279 Magnetic Resonance Imaging Non-invasive method of demonstrating internal anatomy based on the principle that atomic nuclei in a strong magnetic field absorb pulses of radiofrequency energy and emit them as radiowaves which can be reconstructed into computerized images. The concept includes proton spin tomographic techniques. Chemical Shift Imaging,MR Tomography,MRI Scans,MRI, Functional,Magnetic Resonance Image,Magnetic Resonance Imaging, Functional,Magnetization Transfer Contrast Imaging,NMR Imaging,NMR Tomography,Tomography, NMR,Tomography, Proton Spin,fMRI,Functional Magnetic Resonance Imaging,Imaging, Chemical Shift,Proton Spin Tomography,Spin Echo Imaging,Steady-State Free Precession MRI,Tomography, MR,Zeugmatography,Chemical Shift Imagings,Echo Imaging, Spin,Echo Imagings, Spin,Functional MRI,Functional MRIs,Image, Magnetic Resonance,Imaging, Magnetic Resonance,Imaging, NMR,Imaging, Spin Echo,Imagings, Chemical Shift,Imagings, Spin Echo,MRI Scan,MRIs, Functional,Magnetic Resonance Images,Resonance Image, Magnetic,Scan, MRI,Scans, MRI,Shift Imaging, Chemical,Shift Imagings, Chemical,Spin Echo Imagings,Steady State Free Precession MRI
D008297 Male Males
D008969 Molecular Sequence Data Descriptions of specific amino acid, carbohydrate, or nucleotide sequences which have appeared in the published literature and/or are deposited in and maintained by databanks such as GENBANK, European Molecular Biology Laboratory (EMBL), National Biomedical Research Foundation (NBRF), or other sequence repositories. Sequence Data, Molecular,Molecular Sequencing Data,Data, Molecular Sequence,Data, Molecular Sequencing,Sequencing Data, Molecular
D010375 Pedigree The record of descent or ancestry, particularly of a particular condition or trait, indicating individual family members, their relationships, and their status with respect to the trait or condition. Family Tree,Genealogical Tree,Genealogic Tree,Genetic Identity,Identity, Genetic,Family Trees,Genealogic Trees,Genealogical Trees,Genetic Identities,Identities, Genetic,Tree, Family,Tree, Genealogic,Tree, Genealogical,Trees, Family,Trees, Genealogic,Trees, Genealogical
D010641 Phenotype The outward appearance of the individual. It is the product of interactions between genes, and between the GENOTYPE and the environment. Phenotypes
D010903 Pituitary Gland, Anterior The anterior glandular lobe of the pituitary gland, also known as the adenohypophysis. It secretes the ADENOHYPOPHYSEAL HORMONES that regulate vital functions such as GROWTH; METABOLISM; and REPRODUCTION. Adenohypophysis,Anterior Lobe of Pituitary,Anterior Pituitary Gland,Lobus Anterior,Pars Distalis of Pituitary,Adenohypophyses,Anterior Pituitary Glands,Anterior, Lobus,Anteriors, Lobus,Lobus Anteriors,Pituitary Anterior Lobe,Pituitary Glands, Anterior,Pituitary Pars Distalis
D010904 Pituitary Gland, Posterior Neural tissue of the pituitary gland, also known as the neurohypophysis. It consists of the distal AXONS of neurons that produce VASOPRESSIN and OXYTOCIN in the SUPRAOPTIC NUCLEUS and the PARAVENTRICULAR NUCLEUS. These axons travel down through the MEDIAN EMINENCE, the hypothalamic infundibulum of the PITUITARY STALK, to the posterior lobe of the pituitary gland. Neurohypophysis,Infundibular Process,Lobus Nervosus,Neural Lobe,Pars Nervosa of Pituitary,Posterior Lobe of Pituitary,Gland, Posterior Pituitary,Infundibular Processes,Lobe, Neural,Lobes, Neural,Nervosus, Lobus,Neural Lobes,Pituitary Pars Nervosa,Pituitary Posterior Lobe,Posterior Pituitary Gland,Posterior Pituitary Glands,Process, Infundibular,Processes, Infundibular
D011110 Polymorphism, Genetic The regular and simultaneous occurrence in a single interbreeding population of two or more discontinuous genotypes. The concept includes differences in genotypes ranging in size from a single nucleotide site (POLYMORPHISM, SINGLE NUCLEOTIDE) to large nucleotide sequences visible at a chromosomal level. Gene Polymorphism,Genetic Polymorphism,Polymorphism (Genetics),Genetic Polymorphisms,Gene Polymorphisms,Polymorphism, Gene,Polymorphisms (Genetics),Polymorphisms, Gene,Polymorphisms, Genetic
D004268 DNA-Binding Proteins Proteins which bind to DNA. The family includes proteins which bind to both double- and single-stranded DNA and also includes specific DNA binding proteins in serum which can be used as markers for malignant diseases. DNA Helix Destabilizing Proteins,DNA-Binding Protein,Single-Stranded DNA Binding Proteins,DNA Binding Protein,DNA Single-Stranded Binding Protein,SS DNA BP,Single-Stranded DNA-Binding Protein,Binding Protein, DNA,DNA Binding Proteins,DNA Single Stranded Binding Protein,DNA-Binding Protein, Single-Stranded,Protein, DNA-Binding,Single Stranded DNA Binding Protein,Single Stranded DNA Binding Proteins

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