Mort Matthew, Ivanov Dobril, Cooper David N, Chuzhanova Nadia A
Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff, United Kingdom.
Hum Mutat. 2008 Aug;29(8):1037-47. doi: 10.1002/humu.20763.
Nonsense mutations account for approximately 11% of all described gene lesions causing human inherited disease and approximately 20% of disease-associated single-basepair substitutions affecting gene coding regions. Pathological nonsense mutations resulting in TGA (38.5%), TAG (40.4%), and TAA (21.1%) occur in different proportions to naturally occurring stop codons. Of the 23 different nucleotide substitutions giving rise to nonsense mutations, the most frequent are CGA --> TGA (21%; resulting from methylation-mediated deamination) and CAG --> TAG (19%). The differing nonsense mutation frequencies are largely explicable in terms of variable nucleotide substitution rates such that it is unnecessary to invoke differential translational termination efficiency or differential codon usage. Some genes are characterized by numerous nonsense mutations but relatively few if any missense mutations (e.g., CHM) whereas other genes exhibit many missense mutations but few if any nonsense mutations (e.g., PSEN1). Genes in the latter category have a tendency to encode proteins characterized by multimer formation. Consistent with the operation of a clinical selection bias, genes exhibiting an excess of nonsense mutations are also likely to display an excess of frameshift mutations. Tumor suppressor (TS) genes exhibit a disproportionate number of nonsense mutations while most mutations in oncogenes are missense. A total of 12% of somatic nonsense mutations in TS genes were found to occur recurrently in the hypermutable CpG dinucleotide. In a comparison of somatic and germline mutational spectra for 17 TS genes, approximately 43% of somatic nonsense mutations had counterparts in the germline (rising to 98% for CpG mutations). Finally, the proportion of disease-causing nonsense mutations predicted to elicit nonsense-mediated mRNA decay (NMD) is significantly higher (P=1.56 x 10(-9)) than among nonobserved (potential) nonsense mutations, implying that nonsense mutations that elicit NMD are more likely to come to clinical attention.
无义突变约占所有已描述的导致人类遗传性疾病的基因损伤的11%，以及约20%影响基因编码区的与疾病相关的单碱基对替换。导致TGA（38.5%）、TAG（40.4%）和TAA（21.1%）的病理性无义突变与自然发生的终止密码子的比例不同。在导致无义突变的23种不同核苷酸替换中，最常见的是CGA→TGA（21%；由甲基化介导的脱氨作用导致）和CAG→TAG（19%）。不同的无义突变频率在很大程度上可以用可变的核苷酸替换率来解释，因此无需援引不同的翻译终止效率或不同的密码子使用情况。一些基因的特征是有大量无义突变，但错义突变相对较少（如果有的话）（例如CHM），而其他基因则表现出许多错义突变，但无义突变很少（如果有的话）（例如PSEN1）。后一类基因倾向于编码以多聚体形成为特征的蛋白质。与临床选择偏倚的作用一致，表现出过多无义突变的基因也可能表现出过多的移码突变。肿瘤抑制（TS）基因表现出不成比例的无义突变数量，而癌基因中的大多数突变是错义突变。发现TS基因中12%的体细胞无义突变在高度可变的CpG二核苷酸中反复出现。在对17个TS基因的体细胞和种系突变谱的比较中，约43%的体细胞无义突变在种系中有对应物（对于CpG突变上升到98%）。最后，预计引发无义介导的mRNA降解（NMD）的致病无义突变的比例显著高于未观察到的（潜在）无义突变（P=1.56×10^(-9)），这意味着引发NMD的无义突变更有可能受到临床关注。
