The Exon-3 Deletion of the Growth Hormone Receptor (GHR) Gene Still Has a Limited Impact in Clinical Endocrinology

Abstract

Deletion of the GHR-gene exon 3 originated from complex genomic events taking place after the emergence of Old World monkeys, followed by homologous recombination between two retroelements in Homo sapiens (2). Thereafter, it spread throughout human evolution to be present now in approximately 25% of Caucasian chromosomes. For those who think that functional variants become common in populations because of evolutionary advantages, the high frequency of the exon-3-deleted form of the GHR gene in modern Caucasians remains a mystery because nobody has yet proposed a credible hypothesis of the potential advantages of harboring the deletion. To fit with Darwinian theory, this hypothesis should be based on advantageous physiological effects of GH that have been critical for survival, fitness, or reproductive success. Such critical GH-regulated traits may be found in energy fuel regulation, notably hepatic glucose production and free fatty acid release from adipose tissue, during infancy or pregnancy (3–5), or in height and body fat–muscle composition during childhood, adolescence, and early adulthood. Taller individuals with increased muscle mass and better availability of oxidative fuels might be better adapted to hostile environmental conditions. At the protein level, it seems that d3GHR does not affect GH binding to its homodimeric receptor (6), whereas it increases in vitro GH transduction in a nearly dominant manner (7) via intramolecular mechanisms that, to our knowledge, have not been elucidated. Another mystery is the fact that the GHR gene belongs to a gene subset that can show monoallelic expression (8), as observed in blood lymphocytes, which does not obey parental imprinting. If monoallelic GHR expression were also to occur in hepatocytes and chondrocytes, major physiological targets of GH, then heterozygous individuals would randomly express in these cells a nondeleted copy of the GHR gene, an exon-3-deleted (d3) copy or both copies (7). Depending on the proportion of cells exhibiting each expression pattern and on resulting GHR homodimers or heterodimers, the overall effect of exon-3 deletion on GH physiology could be variable among people, despite their having the same d3-non d3 genotype.