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A Transcriptionally Active Human Type II Gonadotropin-Releasing Hormone Receptor Gene Homolog Overlaps Two Genes in the Antisense Orientation on Chromosome 1q.12

Medical Research Council Human Reproductive Sciences Unit (K.M., A.J.P., R.S., T.R.O., R.P.M.), University of Edinburgh Academic Centre, Edinburgh EH16 4SB, United Kingdom; ZymoGenetics Inc. (D.C.), Seattle, Washington 98102; and Medical Research Council Molecular Reproductive Endocrinology Unit (R.P.M.), University of Cape Town Medical School, Observatory 7925, Cape Town, South Africa

Address all correspondence and requests for reprints to: Kevin Morgan, Medical Research Council Human Reproductive Sciences Unit (K.M., A.J.P., R.S., T.R.O., R.P.M.), University of Edinburgh Academic Centre, 49 Little France Crescent, Old Dalkeith Road, Edinburgh EH16 4SB, United Kingdom. E-mail: k.morgan{at}hrsu.mrc.ac.uk.

GnRH-II peptide hormone exhibits complete sequence conservation across vertebrate species, including man. Type-II GnRH receptor genes have been characterized recently in nonhuman primates, but the human receptor gene homolog contains a frameshift, a premature stop codon (UGA), and a 3' overlap of the RBM8A gene on chromosome 1q.12. A retrotransposed pseudogene, RBM8B, retains partial receptor sequence. In this study, bioinformatics show that the human receptor gene promoter overlaps the peroxisomal protein11-ß gene promoter and the premature UGA is positionally conserved in chimpanzee. A CGA [arginine (Arg)] occurs in porcine DNA, but UGA is shifted one codon to the 5' direction in bovine DNA, suggesting independent evolution of premature stop codons. In contrast to marmoset tissue RNA, exon- and strand-specific probes are required to distinguish differently spliced human receptor gene transcripts in cell lines (HP75, IMR-32). RBM8B is not transcribed. Sequencing of cDNAs for spliced receptor mRNAs showed no evidence for alteration of the premature UGA by RNA editing, but alternative splicing circumvents the frameshift to encode a two-membrane-domain protein before this UGA. A stem-loop motif resembling a selenocysteine insertion sequence and a potential alternative translation initiation site might enable expression of further proteins involved in interactions within the GnRH system.

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