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

Stephen E Hamby,David N Cooper,Nadia Chuzhanova,Nick St Thomas

doi:10.1186/1479-7364-5-4-241

Stephen E Hamby, David N Cooper + Show 2 more

Open Access

https://doi.org/10.1186/1479-7364-5-4-241

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Journal: Human genomics	Publication Date: Jan 1, 2011
Citations: 35	License type: cc-by

Affiliation: Nottingham Trent University, Cardiff University

Abstract

'Nonstop' mutations are single base-pair substitutions that occur within translational termination (stop) codons and which can lead to the continued and inappropriate translation of the mRNA into the 3'-untranslated region. We have performed a meta-analysis of the 119 nonstop mutations (in 87 different genes) known to cause human inherited disease, examining the sequence context of the mutated stop codons and the average distance to the next alternative in-frame stop codon downstream, in comparison with their counterparts from control (non-mutated) gene sequences. A paucity of alternative in-frame stop codons was noted in the immediate vicinity (0-49 nucleotides downstream) of the mutated stop codons as compared with their control counterparts (p = 7.81 × 10-4). This implies that at least some nonstop mutations with alternative stop codons in close proximity will not have come to clinical attention, possibly because they will have given rise to stable mRNAs (not subject to nonstop mRNA decay) that are translatable into proteins of near-normal length and biological function. A significant excess of downstream in-frame stop codons was, however, noted in the range 150-199 nucleotides from the mutated stop codon (p = 8.55 × 10-4). We speculate that recruitment of an alternative stop codon at greater distance from the mutated stop codon may trigger nonstop mRNA decay, thereby decreasing the amount of protein product and yielding a readily discernible clinical phenotype. Confirmation or otherwise of this postulate must await the emergence of a clearer understanding of the mechanism of nonstop mRNA decay in mammalian cells.

Highlights

There are currently in excess of 60,000 missense and nonsense mutations listed in the Human Gene Mutation Database (HGMD) that are known to cause, or to be associated with, human inherited disease.[1]
A control dataset was established which comprised 1,692 genes listed in the HGMD
Using the same method as for the original stop codons, we investigated the frequency of occurrence of specific nucleotides surrounding the in-frame stop codon downstream

Summary

Introduction

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]. Until the 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. How nonstop mRNA decay impacts upon naturally occurring human nonstop mutations is unknown but, as is clear from the five disease-associated examples mentioned above, the evidence acquired to date suggests that this may be a gene- and mutation-dependent process.[15] not uncommon, remarkably little is as yet known about the nature and consequences of this type of mutation. With a view to exploring the various possible factors that could impact upon the likelihood of a given nonstop mutation coming to clinical attention, we have performed an analysis of the sequence context of the mutated stop codons and the average distance to the in-frame downstream stop codon in comparison with control (non-mutated) gene sequences

Methods

Results and discussion

Stop codon type

Next STOP codon polyA signals AATAAA ATTAAA