Beltrán-Valero de Bernabé D, Jimenez F J, Aquaron R, Rodríguez de Córdoba S
Unidad de Patología. Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Velázquez 144, 28006-Madrid, Spain.
Am J Hum Genet. 1999 May;64(5):1316-22. doi: 10.1086/302376.
We recently showed that alkaptonuria (AKU) is caused by loss-of-function mutations in the homogentisate 1,2 dioxygenase gene (HGO). Herein we describe haplotype and mutational analyses of HGO in seven new AKU pedigrees. These analyses identified two novel single-nucleotide polymorphisms (INV4+31A-->G and INV11+18A-->G) and six novel AKU mutations (INV1-1G-->A, W60G, Y62C, A122D, P230T, and D291E), which further illustrates the remarkable allelic heterogeneity found in AKU. Reexamination of all 29 mutations and polymorphisms thus far described in HGO shows that these nucleotide changes are not randomly distributed; the CCC sequence motif and its inverted complement, GGG, are preferentially mutated. These analyses also demonstrated that the nucleotide substitutions in HGO do not involve CpG dinucleotides, which illustrates important differences between HGO and other genes for the occurrence of mutation at specific short-sequence motifs. Because the CCC sequence motifs comprise a significant proportion (34.5%) of all mutated bases that have been observed in HGO, we conclude that the CCC triplet is a mutational hot spot in HGO.
我们最近发现，黑尿症（AKU）是由尿黑酸1,2双加氧酶基因（HGO）的功能丧失性突变引起的。在此，我们描述了7个新的AKU家系中HGO的单倍型和突变分析。这些分析确定了两个新的单核苷酸多态性（INV4 + 31A→G和INV11 + 18A→G）和6个新的AKU突变（INV1 - 1G→A、W60G、Y62C、A122D、P230T和D291E），这进一步说明了在AKU中发现的显著等位基因异质性。对HGO中迄今为止描述的所有29个突变和多态性的重新检查表明，这些核苷酸变化并非随机分布；CCC序列基序及其反向互补序列GGG被优先突变。这些分析还表明，HGO中的核苷酸替换不涉及CpG二核苷酸，这说明了HGO与其他基因在特定短序列基序处发生突变的重要差异。由于CCC序列基序在HGO中观察到的所有突变碱基中占很大比例（34.5%），我们得出结论，CCC三联体是HGO中的一个突变热点。
