2016年11月
Exon 10 skipping in ACAT1 caused by a novel c.949G > A mutation located at an exonic splice enhancer site
MOLECULAR MEDICINE REPORTS
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- 巻
- 14
- 号
- 5
- 開始ページ
- 4906
- 終了ページ
- 4910
- 記述言語
- 英語
- 掲載種別
- 研究論文(学術雑誌)
- DOI
- 10.3892/mmr.2016.5819
- 出版者・発行元
- SPANDIDOS PUBL LTD
Beta-ketothiolase deficiency, also known as mitochondrial acetoacetyl-CoA thiolase (T2) deficiency, is an autosomal recessive disease caused by mutations in the acetyl-CoA acetyltransferase 1 (ACAT1) gene. A German T2-deficient patient that developed a severe ketoacidotic episode at the age of 11 months, was revealed to be a compound heterozygote of a previously reported null mutation, c.472A>G (p.N158D) and a novel mutation, c.949G>A (p.D317N), in ACAT1. The c.949G>A mutation was suspected to cause aberrant splicing as it is located within an exonic splicing enhancer sequence (c.947CTGACGC) that is a potential binding site for serine/arginine-rich splicing factor 1. A mutation in this sequence, c.951C>T, results in exon 10 skipping. A minigene construct was synthesized that included exon 9-truncated intron 9-exon 10-truncated intron 10-exon 11, and the splicing of this minigene revealed that the c.949G>A mutant construct caused exon 10 skipping in a proportion of the transcripts. Furthermore, additional substitution of G for C at the first nucleotide of exon 10 (c.941G>C) abolished the effect of the c.949G>A mutation. Transient expression analysis of the c.949G>A mutant cDNA revealed no residual T2 activity in the mutated D317N enzyme. Therefore, c.949G>A (D317N) is a pathogenic missense mutation, and diminishes the effect of an exonic splicing enhancer and causes exon 10 skipping. The present study demonstrates that a missense mutation, or even a synonymous substitution, may disrupt enzyme function by interference with splicing.
- リンク情報
- ID情報
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- DOI : 10.3892/mmr.2016.5819
- ISSN : 1791-2997
- eISSN : 1791-3004
- PubMed ID : 27748876
- Web of Science ID : WOS:000387241600117