Genetics of Growth Hormone Gene Expression

Abstract

The regulation of pituitary GH gene expression depends on binding of transcriptional activation proteins to cis-active DNA sequences preceding the GH-1 gene. The POU homeodomain protein Pit-1 is found in the nuclei of somatotrophs, lactotrophs and thyrotrophs. It fosters differentiation of these pituitary cell types and is required for hormone production by mature cells. In theory, defects in GH secretion can be caused by mutations in the GH-1 promoter sequence or in the gene encoding Pit-1. In the former case, deficiency would be limited to GH, and in the latter deficiencies extend to prolactin (Prl) and thyrotropin (TSH) as well as to GH. Both the Pit-1 gene and the GH-1 gene have been examined in children with extreme growth failure. Studies of kindreds with GH, Prl and TSH deficiency have disclosed a variety of mutations in the Pit-1 gene. These include nonsense mutations, missense mutations that diminish binding and transcriptional activation, and also mutations that appear to increase promoter binding while eliminating transcriptional activation. This latter class of mutation exerts a dominant negative effect in vivo as well as in vitro. There are many examples of deletions in the GH-1 coding sequence. Some are very large and cause the loss of GH-1, chorionic somatomammotropin and placental GH genes. Others are very small, involving only 1 or 2 bases. They produce frameshifts and premature stop signals. All types produce complete deficiency of GH, but antibody development during treatment has proven to be quite variable. The cDNA for the GH-releasing hormone receptor has recently been cloned and sequenced. It is a leading candidate gene for mutations that cause isolated GH deficiency. Additional advances at the basic science level will bring forward other candidate genes whose disruption may account for more common forms of multiple pituitary hormone deficiency involving GH, TSH, adrenocorticotropin and gonadotropins, but not Prl.

A Novel IVS2 −2A>T Splicing Mutation in theGH-1Gene in Familial Isolated Growth Hormone Deficiency Type II in the Spectrum of Other Splicing Mutations in the Russian Population

“…I N RECENT YEARS, OWING to increasing application of recombinant DNA technology in health-related sciences and, in particular, in pediatric endocrinology (1), a whole spectrum of candidate genes involved in the anterior pituitary embryogenesis and normal regulation and function of the GH-IGF-I axis in humans has been disclosed (2)(3)(4). From the point of view of molecular genetics, isolated GH deficiency (IGHD) in children is now considered to be a heterogeneous disorder, comprising a variety of familial and sporadic forms with different modes of inheritance.…”

Conformation of CCAAT/Enhancer-binding Protein α Dimers Varies with Intranuclear Location in Living Cells

“…This altered specificity mutation releases C/EBP␣ from sequestration at the transcriptionally quiescent (11) pericentromeric subdomain, which results in a substantial elevation in C/EBP␣ activation of promoter activity. 2 More naturally, in mouse pituitary cell cultures, C/EBP␣ is redistributed to the euchromatin upon expression of the pituitary-specific transcription factor Pit-1 (19,20), whereas a Pit-1 mutation identified in human patients with combined pituitary hormone deficiency (21,22) is defective in the redistribution of C/EBP␣ (19). Thus, the sequestration of C/EBP␣ at transcriptionally inactive heterochromatin is functionally significant and regulated.…”

Inefficient Secretion of Human H27A-Prolactin, a Mutant That Does Not Bind Zn2+

“…gene (13)(14)(15). Such a finding may be analogous to certain cases of GH deficiency in which the presence of a mutant GH gene suppresses secretion of the product of the normal In the first lane, an Nb2 PRL receptor plasmid was used as a control.…”