Constitutionally Short Stature: Analysis of the Insulin-Like Growth Factor-I Gene and the Human Growth Hormone Gene Cluster

Mullis, Primus-Eugen; Patel, Mukesh R.; Brickell, Paul M.; Brook, C. G. D.

doi:10.1203/00006450-199104000-00017

Cited by 21 publications

(6 citation statements)

References 15 publications

(23 reference statements)

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“…Probes ' random primer labelled probes for the protein coding regions of IGFBP-1 (350 bp), IGFBP-2 (446 bp), IGFBP-3 (475 bp) (Bnnkman et al 1988, Bmkert et al 1989, and IGF-I Ea (725 bp) (Mullís et al 1991) were used. For non-isotopic in situ hybridisation ex¬ periments, anti-sense and sense digoxigenin-labelled probes were made by in vitro transcription with SP6 or T7 RNA polymerase after digestion with Smal or EcoRV respectively.…”

Section: Methodsmentioning

confidence: 99%

Expression of IGF-I and IGF-binding protein genes in cirrhotic liver

Ross

Chew²,

Li³

et al. 1996

Journal of Endocrinology

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The liver plays a central role in the IGF-I axis producing the majority of circulating hormone and some of its binding proteins (IGFBPs). Cirrhosis of the liver is characterised by changes in IGF-I and IGFBPs associated with liver fibrosis and regeneration. We have studied steady state levels of mRNA for the genes in the IGF-I axis in normal and cirrhotic human liver, localised the most highly expressed gene, IGFBP-1, and measured circulating IGFBP-3 by radioimmunoassay (RIA), IGFBP-2 and IGFBP-3 by Western ligand blot (WLB), and protease activity for IGFBP-3 in cirrhotic patients. Messenger RNA for IGF-I, IGFBP-1, IGFBP-2, and IGFBP-3 was detectable by Northern blotting in normal and cirrhotic liver although there was considerable variation in expression. IGFBP-2 and IGFBP-3 tended to be more highly expressed in cirrhotic liver and IGFBP-1 was more highly expressed in normal liver, although there were no significant differences. In normal liver, in situ hybridisation localised IGFBP-1 to hepatocytes. In cirrhotic liver the regenerating nodules showed expression of IGFBP-1 while there was none in fibrotic tissue. Circulating IGFBP-3 levels were low as measured by RIA and WLB but protease activity was only found in one patient. IGFBP-2 levels, assessed by WLB, were similar to the normal serum pool. Our data show that key mRNAs involved in the IGF-I axis continue to be expressed in cirrhotic liver despite end stage liver disease. The low levels of IGFBP-3 do not appear to be due to reduced gene transcription or increased protease activity.

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Section: Methodsmentioning

confidence: 99%

Expression of IGF-I and IGF-binding protein genes in cirrhotic liver

Ross

Chew²,

Li³

et al. 1996

Journal of Endocrinology

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“…The IGF1 locus has been extensively analyzed in several groups of children with "idiopathic" congenital growth retardation; however, no mutations have been identified, leading to the suggestion that IGF-I mutations are not a common cause of growth retardation in humans (145)(146)(147). The debate has been rekindled by the identification of a single case of human IGF1 knockout due to a partial deletion of IGF1.…”

Section: Developmental Phenotypes Of Humans Lacking Igf-i or Igf1rmentioning

confidence: 96%

Distinct and Overlapping Functions of Insulin and IGF-I Receptors

2001

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Targeted gene mutations have established distinct, yet overlapping, developmental roles for receptors of the insulin/IGF family. IGF-I receptor mediates IGF-I and IGF-II action on prenatal growth and IGF-I action on postnatal growth. Insulin receptor mediates prenatal growth in response to IGF-II and postnatal metabolism in response to insulin. In rodents, unlike humans, insulin does not participate in embryonic growth until late gestation. The ability of the insulin receptor to act as a bona fide IGF-II-dependent growth promoter is underscored by its rescue of double knockout Igf1r/Igf2r mice. Thus, IGF-II is a true bifunctional ligand that is able to stimulate both insulin and IGF-I receptor signaling, although with different potencies. In contrast, the IGF-II/cation-independent mannose-6-phosphate receptor regulates IGF-II clearance. The growth retardation of mice lacking IGF-I and/or insulin receptors is due to reduced cell number, resulting from decreased proliferation. Evidence from genetically engineered mice does not support the view that insulin and IGF receptors promote cellular differentiation in vivo or that they are required for early embryonic development. The phenotypes of insulin receptor gene mutations in humans and in mice indicate important differences between the developmental roles of insulin and its receptor in the two species.

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“…IGF-I synthesis Ours and many laboratories have made intense searches to find gene alterations of the IGF-I gene causing GH resistance (189,190). In 1996, Woods et al (152) reported a patient, a 15 year old boy, who had severe intrauterine and postnatal growth retardation, sensorineural deafness, mental retardation and hyperactivity, due to a homozygous deletion of exons 4 and 5 of the IGF-I gene (152).…”

Section: Primary Defects In Igf-imentioning

confidence: 99%

Genetic control of growth

Mullis¹

2005

eur j endocrinol

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The application of the powerful tool molecular biology has made it possible to ask questions not only about hormone production and action but also to characterize many of the receptor molecules that initiate responses to the hormones. We are beginning to understand how cells may regulate the expression of genes and how hormones intervene in regulatory processes to adjust the expression of individual genes. In addition, great strides have been made in understanding how individual cells talk to each other through locally released factors to coordinate growth, differentiation, secretion, and other responses within a tissue. In this review I (1) focus on developmental aspects of the pituitary gland, (2) focus on the different components of the growth hormone axis and (3) examine the different altered genes and their related growth factors and/or regulatory systems that play an important physiological and pathophysiological role in growth. Further, as we have already entered the 'post-genomic' area, in which not only a defect at the molecular level becomes important but also its functional impact at the cellular level, I concentrate in the last part on some of the most important aspects of cell biology and secretion.

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Constitutionally Short Stature: Analysis of the Insulin-Like Growth Factor-I Gene and the Human Growth Hormone Gene Cluster

Abstract: ABSTRACT. It has been suggested that modifications of the IGF

Cited by 21 publications

References 15 publications

Expression of IGF-I and IGF-binding protein genes in cirrhotic liver

Expression of IGF-I and IGF-binding protein genes in cirrhotic liver

Distinct and Overlapping Functions of Insulin and IGF-I Receptors

Genetic control of growth

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