HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 275, Issue 25, 18664-18669, June 23, 2000

This Article Full Text Full Text (PDF) All Versions of this Article: 275/25/18664    most recent M001615200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Pantel, J. Articles by Amselem, S. Search for Related Content PubMed PubMed Citation Articles by Pantel, J. Articles by Amselem, S. Social Bookmarking                      What's this?

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^*

Jacques Pantel^§, Kalotina Machinis, Marie-Laure Sobrier, Philippe Duquesnoy, Michel Goossens, and Serge Amselem^¶

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 GenBank^TM/EMBL Data Bank with accession number(s) AF155912, AF210633, AF209078-209083, and AF211184-211186.

CiteULike

Complore

Connotea

Del.icio.us

Digg

Reddit

Technorati

This article has been cited by other articles:

				G. Kenth, J. A M. Mergelas, and C. G. Goodyer Developmental changes in the human GH receptor and its signal transduction pathways J. Endocrinol., July 1, 2008; 198(1): 71 - 82. [Abstract] [Full Text] [PDF]

				G. Cao, H. Lu, J. Feng, J. Shu, D. Zheng, and Y. Hou Lung Cancer Risk Associated with Thr495Pro Polymorphism of GHR in Chinese Population Jpn. J. Clin. Oncol., April 1, 2008; 38(4): 308 - 316. [Abstract] [Full Text] [PDF]

				B. Raz, M. Janner, V. Petkovic, D. Lochmatter, A. Eble, M. T. Dattani, P. C. Hindmarsh, C. E. Fluck, and P. E. Mullis Influence of Growth Hormone (GH) Receptor Deletion of Exon 3 and Full-Length Isoforms on GH Response and Final Height in Patients with Severe GH Deficiency J. Clin. Endocrinol. Metab., March 1, 2008; 93(3): 974 - 980. [Abstract] [Full Text] [PDF]

				A. Carrascosa, L. Audi, M. Fernandez-Cancio, C. Esteban, P. Andaluz, E. Vilaro, M. Clemente, D. Yeste, M. A. Albisu, and M. Gussinye The Exon 3-Deleted/Full-Length Growth Hormone Receptor Polymorphism Did Not Influence Growth Response to Growth Hormone Therapy over Two Years in Prepubertal Short Children Born at Term with Adequate Weight and Length for Gestational Age J. Clin. Endocrinol. Metab., March 1, 2008; 93(3): 764 - 770. [Abstract] [Full Text] [PDF]

				A. Carrascosa, L. Audi, C. Esteban, M. Fernandez-Cancio, P. Andaluz, M. Gussinye, M. Clemente, D. Yeste, and M. A. Albisu Growth Hormone (GH) Dose, But Not Exon 3-Deleted/Full-Length GH Receptor Polymorphism Genotypes, Influences Growth Response to Two-Year GH Therapy in Short Small-for-Gestational-Age Children J. Clin. Endocrinol. Metab., January 1, 2008; 93(1): 147 - 153. [Abstract] [Full Text] [PDF]

				F. Schreiner, S. Stutte, P. Bartmann, B. Gohlke, and J. Woelfle Association of the Growth Hormone Receptor d3-Variant and Catch-up Growth of Preterm Infants with Birth Weight of Less Than 1500 Grams J. Clin. Endocrinol. Metab., November 1, 2007; 92(11): 4489 - 4493. [Abstract] [Full Text] [PDF]

				C. Schmid, P.-A. Krayenbuehl, R.-L. Bernays, C. Zwimpfer, F. E. Maly, and P. Wiesli Growth Hormone (GH) Receptor Isoform in Acromegaly: Lower Concentrations of GH but Not Insulin-Like Growth Factor-1 in Patients with a Genomic Deletion of Exon 3 in the GH Receptor Gene Clin. Chem., August 1, 2007; 53(8): 1484 - 1488. [Abstract] [Full Text] [PDF]

				R. B. Jensen, S. Vielwerth, T. Larsen, G. Greisen, H. Leffers, and A. Juul The Presence of the d3-Growth Hormone Receptor Polymorphism Is Negatively Associated with Fetal Growth but Positively Associated with Postnatal Growth in Healthy Subjects J. Clin. Endocrinol. Metab., July 1, 2007; 92(7): 2758 - 2763. [Abstract] [Full Text] [PDF]

				P. Fang, S. Riedl, S. Amselem, K. L. Pratt, B. M. Little, G. Haeusler, V. Hwa, H. Frisch, and R. G. Rosenfeld Primary Growth Hormone (GH) Insensitivity and Insulin-Like Growth Factor Deficiency Caused by Novel Compound Heterozygous Mutations of the GH Receptor Gene: Genetic and Functional Studies of Simple and Compound Heterozygous States J. Clin. Endocrinol. Metab., June 1, 2007; 92(6): 2223 - 2231. [Abstract] [Full Text] [PDF]

				G. Kenth, Z. Shao, D. E. C. Cole, and C. G. Goodyer Relationship of the Human Growth Hormone Receptor Exon 3 Genotype with Final Adult Height and Bone Mineral Density J. Clin. Endocrinol. Metab., February 1, 2007; 92(2): 725 - 728. [Abstract] [Full Text] [PDF]

				J. D. McKay, R. Kaaks, M. Johansson, C. Biessy, F. Wiklund, K. Balter, H.-O. Adami, C. Boillot, L. Gioia-Patricola, F. Canzian, et al. Haplotype-Based Analysis of Common Variation in the Growth Hormone Receptor Gene and Prostate Cancer Risk Cancer Epidemiol. Biomarkers Prev., January 1, 2007; 16(1): 169 - 173. [Abstract] [Full Text] [PDF]

				L. Audi, C. Esteban, A. Carrascosa, R. Espadero, A. Perez-Arroyo, R. Arjona, M. Clemente, H. Wollmann, L. Fryklund, L. A. Parodi, et al. Exon 3-Deleted/Full-Length Growth Hormone Receptor Polymorphism Genotype Frequencies in Spanish Short Small-for-Gestational-Age (SGA) Children and Adolescents (n = 247) and in an Adult Control Population (n = 289) Show Increased fl/fl in Short SGA J. Clin. Endocrinol. Metab., December 1, 2006; 91(12): 5038 - 5043. [Abstract] [Full Text] [PDF]

				R. Pfaffle Genetics of growth in the normal child Eur. J. Endocrinol., November 1, 2006; 155(suppl_1): S27 - S33. [Abstract] [Full Text] [PDF]

				W. F. Blum, K. Machinis, E. P. Shavrikova, A. Keller, H. Stobbe, R. W. Pfaeffle, and S. Amselem The Growth Response to Growth Hormone (GH) Treatment in Children with Isolated GH Deficiency Is Independent of the Presence of the Exon 3-Minus Isoform of the GH Receptor J. Clin. Endocrinol. Metab., October 1, 2006; 91(10): 4171 - 4174. [Abstract] [Full Text] [PDF]

				A. Carrascosa, C. Esteban, R. Espadero, M. Fernandez-Cancio, P. Andaluz, M. Clemente, L. Audi, H. Wollmann, L. Fryklund, L. Parodi, et al. The d3/fl-Growth Hormone (GH) Receptor Polymorphism Does Not Influence the Effect of GH Treatment (66 {micro}g/kg per Day) or the Spontaneous Growth in Short Non-GH-Deficient Small-for-Gestational-Age Children: Results from a Two-Year Controlled Prospective Study in 170 Spanish Patients J. Clin. Endocrinol. Metab., September 1, 2006; 91(9): 3281 - 3286. [Abstract] [Full Text] [PDF]

				R. G. Rosenfeld The Pharmacogenomics of Human Growth. J. Clin. Endocrinol. Metab., March 1, 2006; 91(3): 795 - 796. [Full Text] [PDF]

				A. A. L. Jorge, F. G. Marchisotti, L. R. Montenegro, L. R. Carvalho, B. B. Mendonca, and I. J. P. Arnhold Growth Hormone (GH) Pharmacogenetics: Influence of GH Receptor Exon 3 Retention or Deletion on First-Year Growth Response and Final Height in Patients with Severe GH Deficiency J. Clin. Endocrinol. Metab., March 1, 2006; 91(3): 1076 - 1080. [Abstract] [Full Text] [PDF]

				G. Binder, F. Baur, R. Schweizer, and M. B. Ranke The d3-Growth Hormone (GH) Receptor Polymorphism Is Associated with Increased Responsiveness to GH in Turner Syndrome and Short Small-for-Gestational-Age Children J. Clin. Endocrinol. Metab., February 1, 2006; 91(2): 659 - 664. [Abstract] [Full Text] [PDF]

				R. N. Nurtdinov, I. I. Artamonova, A. A. Mironov, and M. S. Gelfand Low conservation of alternative splicing patterns in the human and mouse genomes Hum. Mol. Genet., June 1, 2003; 12(11): 1313 - 1320. [Abstract] [Full Text] [PDF]

				J. Pantel, J. Grulich-Henn, M. Bettendorf, C. J. Strasburger, U. Heinrich, and S. Amselem Heterozygous Nonsense Mutation in Exon 3 of the Growth Hormone Receptor (GHR) in Severe GH Insensitivity (Laron Syndrome) and the Issue of the Origin and Function of the GHRd3 Isoform J. Clin. Endocrinol. Metab., April 1, 2003; 88(4): 1705 - 1710. [Abstract] [Full Text] [PDF]

				M. Gebre-Medhin, L.-G. Kindblom, H. Wennbo, J. Tornell, and J. M. Meis-Kindblom Growth Hormone Receptor Is Expressed in Human Breast Cancer Am. J. Pathol., April 1, 2001; 158(4): 1217 - 1222. [Abstract] [Full Text] [PDF]

				S. Papin, P. Duquesnoy, C. Cazeneuve, J. Pantel, M. Coppey-Moisan, C. Dargemont, and S. Amselem Alternative splicing at the MEFV locus involved in familial Mediterranean fever regulates translocation of the marenostrin/pyrin protein to the nucleus Hum. Mol. Genet., December 1, 2000; 9(20): 3001 - 3009. [Abstract] [Full Text] [PDF]