A point mutation in the POU-specific portion of the human gene that encodes the tissue-specific POU-domain transcription factor, Pit-1, results in hypopituitarism, with deficiencies of growth hormone, prolactin, and thyroid-stimulating hormone. In two unrelated Dutch families, a mutation in Pit-1 that altered an alanine in the first putative alpha helix of the POU-specific domain to proline was observed. This mutation generated a protein capable of binding to DNA response elements but unable to effectively activate its known target genes, growth hormone and prolactin. The phenotype of the affected individuals suggests that the mutant Pit-1 protein is competent to initiate other programs of gene activation required for normal proliferation of somatotrope, lactotrope, and thyrotrope cell types. Thus, a mutation in the POU-specific domain of Pit-1 has a selective effect on a subset of Pit-1 target genes.
Somatomedins (SM) or insulin-like growth factors (IGF) constitute a heterogeneous group of peptides with important growth-promoting effects in vitro as well as in vivo. Amino acid sequences have been determined for only two of them, IGF-I and IGF-II, which are highly homologous. IGF-I, which is identical with SM-C, is composed of 70 amino acid residues and IGF-II contains 73 amino acids and may be identical with SM-A. Other peptides with different charge properties but with similar SM-like or insulin-like behaviour in biological and receptor assays, have been described but have not yet been fully characterized. The liver is known to be a major site of production of these peptides, but many other tissues--especially in the fetus--may synthesize them as well. We report here the nucleotide sequence of a human liver cDNA encoding the complete amino acid sequence of IGF-I. The IGF-I coding region is flanked by sequences encoding an amino-terminal peptide of at least 25 amino acid residues and a carboxyl-terminal peptide of 35 amino acids. This provides evidence that IGF-I is synthesized as a precursor protein and that formation of IGF-I from this precursor requires proteolytic processing at both ends.
Background: Traditionally, measurement of plasma IGF-I and more recently of IGFBP-3 are used to distinguish GHD from idiopathic short stature in slowly growing children, using a single blood sample. In earlier studies it was claimed that IGFBP-3 was superior to IGF-I, but more recently doubts around this claim have arisen. The role of serum IGF-II has never been studied extensively. On theoretical grounds, it can also be hypothesized that molar ratios of these peptides might be of additional value. Design: Retrospective, multicentre, cohort study. Patients: 96 children evaluated for short stature. Methods: Serum IGF-I, IGF-II, IGFBP-3 and various molar ratios were, after correction for age and sex using SD scores, compared to the maximum serum GH peak after two standard provocation tests using four different methods (t-test, χ2, likelihood ratios and ROC curves). In addition, the correlations between these parameters and the short-term (1 year) and long-term (3 years) response to GH therapy were calculated. Results: IGF-I performed better than IGFBP-3, but the best results were achieved by the molar ratio IGF-I:IGF-II. However, IGFBP-3 correlated better with the short-term response to GH therapy than IGF-I or the ratios, and none of the parameters investigated was found to be related to the response of long-term GH therapy.
Transforming growth factor beta (TGF-beta), a potent fibrogenic cytokine, is secreted in latent form. We examined which cell type in both normal and carbon tetrachloride (CCl4)-induced fibrotic rat liver bears surface type II IGF/mannose 6-phosphate (IGF-II/M6P) receptor, known to facilitate activation of TGF-beta. In addition, the role of the IGF-II/M6P receptor in activation of latent TGF-beta was investigated in a coculture system with sinusoidal endothelial cells. Northern hybridization analysis for IGF-II/M6P receptor messenger RNA (mRNA) was performed on total RNA of different isolated and purified liver cell types. In normal liver, cells expressed little IGF-II/M6P receptor mRNA. In fibrotic liver, we found significant expression only in fat-storing cells. The presence of IGF-II/M6P receptors was established by [125I]IGF-II binding assays on freshly isolated fat-storing cells from normal and CCl4-exposed rat livers. We found specific binding of [125I]IGF-II only on CCl4 exposed fat-storing cells. As determined by polyacrylamide gel electrophoresis after affinity labeling, the specific binding involved 220 kD type II IGF receptors. Scatchard analysis revealed the presence of 3,043 +/- 1,378 IGF-II/M6P high-affinity receptors/fat-storing cell, with a Kd of 387 = 165 pmol/L. With a mink lung epithelial cell (Mv1Lu) proliferation inhibition assay, inhibition of proliferation (a measure of active TGF-beta function) was determined using conditioned media of activated fat-storing cells, cocultures of fat-storing cells, and endothelial cells and pure endothelial cell cultures.(ABSTRACT TRUNCATED AT 250 WORDS)
The rate at which girls progress through the stages of puberty in relation to body fat mass and body fat distribution and its relation to their hormonal profiles was studied. Sixty-eight schoolgirls participated in a longitudinal study during 3 yr. The girls were divided into subgroups with increasing skinfold thicknesses and waist-hip ratio. They were also grouped depending on Tanner's breast development classification (M2 and M3). The age at M2 was only marginally correlated with the menarcheal age, but the age at M2 and the time interval from that age to menarche was negatively correlated. Age at the onset of puberty was not related to body fat mass or distribution. The rate of pubertal development after pubertal stage M3 was negatively related to the body fat mass. Age at M2 was only correlated with estrone (E1), while the rate of pubertal development was associated with higher FSH, E1, estradiol (E2), the fraction of E2 that was not bound to sex-hormone-binding globulin (non-sex-hormone-binding globulin bound E2) and androstenedione plasma levels at the onset of puberty. Body fat distribution, rather than body fat mass was related to the total and the non-sex-hormone-binding globulin bound plasma levels of E2 and testosterone at the onset of puberty. Changes in body fat distribution in early female puberty were chiefly related to the waist circumferences. We found no evidence that body fat mass or body fat distribution triggers the onset of puberty. Body fat distribution was related to early pubertal endocrine activity. Body fat mass was negatively related to the rate of pubertal development toward menarche, but no clear indications for an endocrine-related process is found. We conclude that onset of puberty and menarche are not parallel pubertal events, and that early pubertal plasma E1, E2 and androstenedione levels are predictors for the rate of pubertal development toward menarche. We propose that the control of the onset of puberty and maturation of the hypothalamic-pituitary gonadal axis, with regard to negative feedback control, are at least partially independent. This induces on the average a "catch up" pubertal maturation in girls with a late onset of puberty.
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