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J. Biol. Chem., Vol. 275, Issue 25, 18664-18669, June 23, 2000
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From the Institut National de la Santé et de la Recherche
Médicale, Unité 468, Hôpital Henri Mondor,
94010 Créteil Cedex, France
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 nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EMBL Data Bank with accession number(s) AF155912, AF210633, AF209078-209083, and
AF211184-211186.
Species-specific Alternative Splice Mimicry at the Growth Hormone
Receptor Locus Revealed by the Lineage of Retroelements during Primate
Evolution
A NOVEL MECHANISM ACCOUNTING FOR PROTEIN DIVERSITY BETWEEN AND
WITHIN SPECIES*
§,,
*
This work was supported by an institutional grant from the
INSERM.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
These authors contributed equally to this work.
§
Recipient of a fellowship from the Institut National de la
Santé et de la Recherche Médicale.
¶
To whom correspondence should be addressed. E-mail:
amselem@ im3.inserm.fr.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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