ALTERNATIVE SPLICING OF EXON-3 OF THE HUMAN GROWTH-HORMONE RECEPTOR IS THE RESULT OF AN UNUSUAL GENETIC-POLYMORPHISM

Two isoforms of the human growth hormone receptor (hGHR), which differ in the presence (hGHRwt) or absence (hGHRd3) of exon 3, are expressed in the placenta, Specifically, three expression patterns are observed : only hGHRwt, only hGHRd3, or an approximately 1:1 combination of bot h isoforms. We investigated several potential regulatory mechanisms wh ich might account for the expression of the hGHR isoforms, The frequen cy of hGHRd3 expression did not change when placentas from differing s tages of gestation were examined, suggesting splicing was not developm entally regulated. However, when hGHR isoform expression patterns were examined in each component of a given placenta, it was evident that a lternative splicing of exon 3 is individual-specific. Surprisingly, th e individual-specific regulation of hGHR isoforms appears to be the re sult of a polymorphism in the hGHR gene. We analyzed hGHRwt and hGHRd3 expression in Hutterite pedigrees, and our results are consistent wit h a simple Mendelian inheritance of two differing alleles in which exo n 3 is spliced in an ''all-or-none'' fashion. We conclude the alternat ive splicing of exon 3 in hGHR transcripts is the result of an unusual polymorphism which significantly alters splicing of the hGHR transcri pt and that the relatively high frequency (approximate to 10%) of homo zygous hGHRd3 expression suggests the possibility it may play a role i n polygenic determined events.