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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
35
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pubmed:dateCreated |
2008-8-25
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pubmed:abstractText |
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.
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pubmed:grant |
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pubmed:commentsCorrections |
http://linkedlifedata.com/resource/pubmed/commentcorrection/18586677-10049361,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18586677-10694877,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18586677-10757789,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18586677-11124808,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18586677-11836331,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18586677-11967553,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18586677-12655557,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18586677-12720086,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18586677-12824367,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18586677-14988388,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18586677-15208309,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18586677-1577277,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18586677-17000773,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18586677-17576688,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18586677-2825811,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18586677-3627992,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18586677-6269091,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18586677-7489484,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18586677-7585252,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18586677-7667103,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18586677-7958850,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18586677-8139654,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18586677-8261509,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18586677-8290338,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18586677-8530604,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18586677-8632829,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18586677-8674830,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18586677-9130721,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18586677-9175738,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18586677-9689050,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18586677-9700205,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18586677-9799079
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Aug
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pubmed:issn |
0021-9258
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
29
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pubmed:volume |
283
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
23619-26
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pubmed:dateRevised |
2011-11-17
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pubmed:meshHeading |
pubmed-meshheading:18586677-Animals,
pubmed-meshheading:18586677-Cell Line,
pubmed-meshheading:18586677-Exons,
pubmed-meshheading:18586677-Genetic Diseases, Inborn,
pubmed-meshheading:18586677-Growth Hormone,
pubmed-meshheading:18586677-Humans,
pubmed-meshheading:18586677-Mutation,
pubmed-meshheading:18586677-Nuclear Proteins,
pubmed-meshheading:18586677-RNA Splicing,
pubmed-meshheading:18586677-RNA-Binding Proteins,
pubmed-meshheading:18586677-Rats,
pubmed-meshheading:18586677-Ribonucleoproteins
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pubmed:year |
2008
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pubmed:articleTitle |
Growth hormone deficiency and splicing fidelity: two serine/arginine-rich proteins, ASF/SF2 and SC35, act antagonistically.
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pubmed:affiliation |
Department of Biological Sciences, Vanderbilt University, 2301 Vanderbilt Pl., Nashville, TN 37235, USA.
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pubmed:publicationType |
Journal Article,
Research Support, N.I.H., Extramural
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