Isolated growth hormone deficiency type II caused by a point mutation that alters both splice site strength and splicing enhancer function.
A heterozygous single base mutation in the human growth hormone (GH) gene (GH-1) was identified in a family presenting with isolated GH deficiency type II (IGHD II). Affected individuals have a guanine to adenine transition at the first nucleotide of exon 3 (E3+1 G-->A) that results in exon skipping and production of a dominant-negative 17.5-kDa isoform. We show that the mechanistic basis for exon skipping is due to the unique position of this mutation because it weakens the 3' splice site and simultaneously disrupts a splicing enhancer located within the first seven bases of exon 3. A G-->T mutation at this same position not only affects splicing but also results in a premature stop codon for those transcripts that include exon 3. Thus, mutations that alter the first nucleotide of exon 3 illustrate the various mechanisms by which changes in sequence can cause disease: splice site selection, splicing enhancer function, messenger RNA decay, missense mutations, and nonsense mutations. For IGHD II, only exon skipping leads to production of the dominant-negative isoform, with increasing skipping correlating with increasing disease severity.
Department of Biological Sciences, Vanderbilt University, Nashville, TN 37235, USA.
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Shariat
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Holladay
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Cleary
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Phillips
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Patton
D002478:Cells, Cultured; D002675:Child, Preschool; D005091:Exons / Q000235:genetics; D005260:Female; D019382:Human Growth Hormone / Q000172:deficiency*; D006801:Humans; D007223:Infant; D008297:Male; D008659:Metabolic Diseases / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D017354:Point Mutation / Q000235:genetics*; D034622:RNA Interference; D022821:RNA Splice Sites / Q000235:genetics*; D012326:RNA Splicing / Q000235:genetics*
D022821:RNA Splice Sites; D019382:Human Growth Hormone