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      Isolated Growth Hormone Deficiency and the GH-1 Gene: Update 2002

      Hormone Research in Paediatrics

      S. Karger AG

      GH promotor, Growth hormone, IGHD, <italic>GH-1</italic> gene

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          This short review will focus on the mechanisms which are thought to be directly involved in GH expression and particularly on the monogenetic disorders which were shown to cause isolated growth hormone deficiency (IGHD) due to insufficient expression of GH. The overwhelming majority of genetic defects detected in isolated growth hormone deficiency (IGHD) are mutations of the coding region of the GH-1 gene which belongs to a five genes containing gene cluster located on 17q22–24. Depending on the type of the GH-1 gene mutation, the mode of inheritance is recessive or dominant. The promotor region of the GH-1 gene which encompasses the 300 bp of the 5′ flanking region is highly polymorphic, but the functionally important cis-acting elements are conserved. This sequence is sufficient to control GH expression in cultured cells, but not in transgenic mice: the human GH locus control region, an enhancer region of the GH-1 gene located approximately 15–32 kB upstream of the GH-1 coding region was shown to direct pituitary-specific, high-level GH expression in vivo. Promotion of the GH expression needs the coordinate binding of pituitary-specific (i.e., POU1F1) and ubiquitous trans-acting factors to the cis-acting elements. The mutational analysis of trans-acting factors and cis-acting elements of the GH-1 gene has so far not established any defect outside the coding region as the genetic basis of IGHD except for POU1F1 mutations which cause multiple pituitary hormone deficiency including GHD. Several mutations of the GHRH-receptor gene were shown to result in severe IGHD. In the future, the discovery of new defects of the GH expression machinery will add to our understanding of how GH is sufficiently supplied to the organism and will hopefully simplify and improve the diagnostic approach in a subset of children with IGHD.

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          Most cited references 5

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          GTPase inhibiting mutations activate the alpha chain of Gs and stimulate adenylyl cyclase in human pituitary tumours.

          A subset of growth hormone-secreting human pituitary tumours carries somatic mutations that inhibit GTPase activity of a G protein alpha chain, alpha(s). The resulting activation of adenylyl cyclase bypasses the cells' normal requirement for trophic hormone. Amino acids substituted in the putative gsp oncogene identify a domain of G protein alpha-chains required for intrinsic ability to hydrolyse GTP. This domain may serve as a built-in counter-part of the separate GTPase-activating proteins required for GTP hydrolysis by small GTP-binding proteins such as p21ras.
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            Involvement of follicular stem cells in forming not only the follicle but also the epidermis.

            The location of follicular and epidermal stem cells in mammalian skin is a crucial issue in cutaneous biology. We demonstrate that hair follicular stem cells, located in the bulge region, can give rise to several cell types of the hair follicle as well as upper follicular cells. Moreover, we devised a double-label technique to show that upper follicular keratinocytes emigrate into the epidermis in normal newborn mouse skin, and in adult mouse skin in response to a penetrating wound. These findings indicate that the hair follicle represents a major repository of keratinocyte stem cells in mouse skin, and that follicular bulge stem cells are potentially bipotent as they can give rise to not only the hair follicle, but also the epidermis.
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              Heritable Disorders of Pituitary Development

               J S Parks (1999)

                Author and article information

                Horm Res Paediatr
                Hormone Research in Paediatrics
                S. Karger AG
                November 2002
                17 November 2004
                : 58
                : Suppl 3
                : 2-6
                University Children’s Hospital, Tübingen, Germany
                66476 Horm Res 2002;58(suppl 3):2–6
                © 2002 S. Karger AG, Basel

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                Page count
                Figures: 2, References: 38, Pages: 5
                Molecular Biology of the GH-IGF System


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