Fukao T, Yamaguchi S, Scriver C R, Dunbar G, Wakazono A, Kano M, Orii T, Hashimoto T
Department of Pediatrics, Gifu University School of Medicine, Japan.
Hum Mutat. 1993;2(3):214-20. doi: 10.1002/humu.1380020310.
We describe mutations identified in stored skin fibroblast cell lines from two original probands (JB and JM), first reported with 2-methylacetoacetic aciduria, and shown later to have a deficiency of the K(+)-activated enzyme, mitochondrial acetoacetyl-coenzyme A thiolase (T2). JB is homozygous for a 4-base insertion (GCAG) which is derived mutation. The primary mutation is an AG/gt to AG/gc transition at the 5'-splice-junction site in intron 11. An alternative splice site 4 bp downstream (Ggcag/gt) is used which causes a frame shift and replaces 39 C-terminal residues by 70 nonfunctional residues. JM is homozygous for a mutation in the translation-initiation codon (ATG to AAG). By expression analyses the JB mutation (IVS11nt2) causes an unstable T2 polypeptide and the JM mutation (M1K) severely impairs T2 mRNA translation. The JB allele associates with Dutch ancestry (no consanguinity) and the JM allele with Chilean ancestry (distant consanguinity).
我们描述了在来自两名原发病例（JB和JM）的储存皮肤成纤维细胞系中鉴定出的突变，这两名病例最初报告患有2-甲基乙酰乙酸尿症，后来发现缺乏K(+)激活酶——线粒体乙酰乙酰辅酶A硫解酶（T2）。JB为一个4碱基插入（GCAG）的纯合子，这是一个衍生突变。原发性突变是内含子11中5'-剪接连接位点处的AG/gt到AG/gc转换。使用了下游4 bp处的一个替代剪接位点（Ggcag/gt），这导致了移码，并使39个C端残基被70个无功能残基取代。JM是翻译起始密码子（ATG到AAG）突变的纯合子。通过表达分析，JB突变（IVS11nt2）导致T2多肽不稳定，而JM突变（M1K）严重损害T2 mRNA的翻译。JB等位基因与荷兰血统（无血缘关系）相关，JM等位基因与智利血统（远亲血缘关系）相关。
