Species-specific Alternative Splice Mimicry at the Growth Hormone Receptor Locus Revealed by the Lineage of Retroelements during Primate Evolution

Abstract

In humans, growth hormone receptor (GHR) transcripts exist in two isoforms differing by the retention (GHRfl) or exclusion (GHRd3) of exon 3, whereas in mice GHRfl is solely expressed. This species-specific expression pattern is believed to result from an alternative splice event that, on the basis of conflicting data obtained in humans, has been considered to be tissue-, developmentally, and/or individual-specific. To decipher the molecular basis of this unusual trait, we isolated a 6.8-kilobase fragment spanning exon 3 from individuals expressing GHRfl. Sequence analysis revealed the existence of two 99% identical retroelements flanking this exon. Unexpectedly, individuals expressing GHRd3 displayed a 2.7-kilobase deletion involving exon 3, which most likely results from an ancestral homologous recombination between the two retroelements. The lineage of these retroelements during primate evolution revealed the species specificity of the GHRd3 allele. These findings led us to propose a model underlying the existence of the sole GHRfl allele in most species. Such a retrovirus-mediated alternative splice mimicry, which clears up several as yet unexplained phenomena (i.e. the above-mentioned expression data, the Mendelian inheritance of GHR expression patterns, and the deletion of nonconsecutive exons in growth hormone resistant patients), represents a novel physiological mechanism accounting for protein diversity between and within species.

The role of GHR and IGF1 genes in the genetic determination of African pygmies’ short stature

“…Most of the primers were designed using Primer 3 26 and others were adapted from previous studies. 21,27,28 Primer sequences can be found in Supplementary Table S1. Amplifications were performed using standard PCR conditions (available upon request).…”

Pegvisomant in combination with long-acting somatostatin analogues in acromegaly: the role of the GH receptor deletion of exon 3

“…The required dose A polymorphism of the GHR that lacks exon 3 (d3-GHR) during splicing is common in the general population. About half of the population is homozygous for the full-length GHR (fl-GHR), 30-40% is heterozygous for d3-GHR and 10-20% is homozygous for this deletion (7,8,9). It has been reported that the d3-GHR polymorphism shows a comparable distribution between different cohorts of acromegalic patients (6,10,11,12).…”

Biological Determinants of Responsiveness to Growth Hormone: Pharmacogenomics and Personalized Medicine

“…Polymorphisms of the GHR gene have been reported in the general population and have been described in exons 3, 6 and 10 [31]. While the latter two are classical single nucleotide polymorphisms, the polymorphism in exon 3 is an unusual one, leading to retention (full-length, fl; GHRfl) or deletion of exon 3 (d3; GHRd3), which encodes a 22-amino-acid residue sequence in the extracellular domain [37,38]. GHRd3 has recently been associated with the degree of height increase in response to GH replacement in children born short for gestational age (SGA), in those with ISS, and in a GHD population [39,40].…”