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The human growth hormone receptor (hGHR) is encoded by exons 2-10 of the hGHR gene on chromosome 5p13.1-p12. There are several different 5' untranslated region (5'UTR) variants of hGHR mRNA (V1-V9) that all encode the same protein. We have recently mapped the V1-V9 5'UTR sequences within 40 kb of the 5' flanking region of the hGHR gene. Seven of the exons are clustered within two small modules, module A (V2-V9-V3) and module B (V7-V1-V4-V8), approximately 38 kb and approximately 18 kb respectively upstream of exon 2 of the coding region; V6 lies midway between the two modules and V5 is adjacent to exon 2. We now report the existence of two subvariant V3 exons, one upstream of module A (exon V3b) and one midway between module B and exon 2 (exon V3a/b). Both have sequences homologous to Alu elements. In addition, we determined the alternative splicing mechanisms that produce three different mRNAs from these exons: V3c (from the V3 exon in module A) or V3a and V3b (from a combination of exon V3 and the Alu-containing V3 subvariant exons). hGHR expression is under developmental- and tissue-specific regulation: module A-derived mRNAs are widely expressed in human tissues, while module B-derived mRNAs are only detectable in postnatal liver. Expression of the variant V3 mRNAs is similar to those from module A, being produced ubiquitously in human fetal and postnatal tissues, with V3c always the major variant detected. The Alu-containing mRNAs (V3a and V3b) are also detectable in baboon and rhesus tissues, in accordance with the finding of Alu elements throughout the primate genome. In summary, we have mapped the relative locations of two new 5'UTR exons within the 5' flanking region of the hGHR gene and described the derivation and expression patterns for two variant hGHR mRNAs from these primate-specific exons. The introduction of Alu elements has contributed to the evolution of the primate GHR gene as a highly complex transcriptional unit.

Alu elements in human growth hormone receptor gene 5' untranslated region exons