A meta-analysis of single base-pair substitutions in translational termination codons ('nonstop' mutations) that cause human inherited disease

There are currently in excess of 60,000 missense and nonsense mutations (in nearly 4,000 different genes) listed in the Human Gene Mutation Database (HGMD) that are known to cause, or to be associated with, human inherited disease [1]. In addition, there are 119 examples of mutations (in 87 different genes) that occur within stop codons, a category of mutation which therefore constitutes ~0.2% per cent of codon-changing mutations [1]. Such lesions have been termed 'nonstop', 'nostop' or 'readthrough' mutations on the basis that the loss of the normal translational termination (stop) codon is likely to lead to continued translation of the mRNA further downstream into the 3'-untranslated region (UTR).Although many authors tacitly assume that the normal open reading frame will simply be extended until the next in-frame stop codon is encountered, too few human nonstop mutations have so far been characterised to allow any general conclusions to be drawn as to their likely phenotypic consequences at either the mRNA or the protein level. In three reported cases, however (namely, those nonstop mutations in the gene encoding ribosomal protein S19 [RPS19], causing Diamond-Blackfan anaemia,[2] the F10 gene causing factor X deficiency [3] and the foxhead box E3 [FOXE3] gene causing anterior segment dysgenesis [4]), the levels of the mutant mRNA transcripts were found to be dramatically lower than those of their wild-type counterparts. By contrast, the mRNA level associated with a nonstop mutation in the 3-beta-hydroxy-delta-5-steroid dehyrogenase (HSD3B2) gene causing adrenal hyperplasia was found to be near normal, although both HSD3B2 enzymatic activity and antigen (associated with a predicted 467 amino-acid protein, extended by 95 residues beyond the wild-type length) were found to be dramatically reduced [5]. Similarly, in the case of a nonstop mutation in the thymidine phosphorylase (TYMP) gene responsible for mitochondrial neurogastrointestinal encephalomyopathy, the mRNA