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J. Biol. Chem., Vol. 283, Issue 35, 23619-23626, August 29, 2008

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Growth Hormone Deficiency and Splicing Fidelity

TWO SERINE/ARGININE-RICH PROTEINS, ASF/SF2 AND SC35, ACT ANTAGONISTICALLY^*

Amanda S. Solis¹, Rui Peng¹, J. Barrett Crawford, John A. Phillips, III, and James G. Patton²

From the Departments of Biological Sciences and Pediatrics, Vanderbilt University, Nashville, Tennessee 37235

The majority of mutations that cause isolated growth hormone deficiency type II are the result of aberrant splicing of transcripts encoding human growth hormone. Such mutations increase skipping of exon 3 and encode a 17.5-kDa protein that acts as a dominant negative to block secretion of full-length protein produced from unaffected alleles. Previously, we identified a splicing regulatory element in exon 3 (exonic splicing enhancer 2 (ESE2)), but we had not determined the molecular mechanism by which this element prevents exon skipping. Here, we show that two members of the serine/arginine-rich (SR) protein superfamily (ASF/SF2 and SC35) act antagonistically to regulate exon 3 splicing. ASF/SF2 activates exon 3 inclusion, but SC35, acting through a region just downstream of ESE2, can block such activation. These findings explain the disease-causing mechanism of a patient mutation in ESE2 that creates a functional SC35-binding site that then acts synergistically with the downstream SC35 site to produce pathological levels of exon 3 skipping. Although the precedent for SR proteins acting as repressors is established, this is the first example of a patient mutation that creates a site through which an SR protein represses splicing.

Received for publication, December 13, 2007 , and in revised form, June 26, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants GM 62487m (to J. G. P.) and DK 35592 (to J. A. P.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ These authors contributed equally to this work.

² To whom correspondence should be addressed: Dept. of Biological Sciences, 2301 Vanderbilt Pl., Station B, Box 1820, Nashville, TN 37235. Fax: 615-343-6707; E-mail: james.g.patton{at}vanderbilt.edu.

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