title: Growth hormone deficiency and splicing fidelity: two serine/arginine-rich proteins, ASF/SF2 and SC35, act antagonistically.
abstract: 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.
authors.affiliation: Department of Biological Sciences, Vanderbilt University, 2301 Vanderbilt Pl., Nashville, TN 37235, USA.
authors.forename: Amanda S
authors.initials: AS
authors.lastname: Solis
authors.forename: Rui
authors.initials: R
authors.lastname: Peng
authors.forename: J Barrett
authors.initials: JB
authors.lastname: Crawford
authors.forename: John A
authors.initials: JA
authors.lastname: Phillips
authors.forename: James G
authors.initials: JG
authors.lastname: Patton
mesh_terms: D000818:Animals; D002460:Cell Line; D005091:Exons / Q000235:genetics; D030342:Genetic Diseases, Inborn / Q000235:genetics / Q000378:metabolism*; D013006:Growth Hormone / Q000172:deficiency* / Q000378:metabolism*; D006801:Humans; D009154:Mutation; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012326:RNA Splicing / Q000235:genetics; D016601:RNA-Binding Proteins; D051381:Rats; D012261:Ribonucleoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000068103:Serine-Arginine Splicing Factors
chemical_list: D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; D012261:Ribonucleoproteins; C073288:SRSF2 protein, human; D000068103:Serine-Arginine Splicing Factors; D013006:Growth Hormone