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- AHC, adrenal hypoplasia congenita
- APC, adenomatous polyposis coli
- ATMDS, alpha thalassaemia myelodysplasia syndrome
- NBS, Nijmegen breakage syndrome
- NMD, nonsense mediated decay
- PBD, peroxisome-biogenesis disorder
Nonsense mutations located in the 5′ end of the coding sequence of a gene are commonly considered to be null alleles. Not only do such mutations result in the production of a truncated and usually inactive protein product, but premature stop codon mutations that occur upstream of the last exon–exon junction are also known to activate nonsense mediated decay (NMD) which results in the specific degradation of the affected mRNA.1,2 However, several mechanisms may allow either fully or partially functional protein to be produced from alleles containing a premature stop codon mutation and this phenomenon may lead to considerable amelioration of the resulting phenotype.
First, translational decoding (miscoding) of the stop codon as a sense codon, which can occur naturally due to the context of the stop codon,3 may result in low level “leaky” expression of full length protein. Although no examples of stop codon readthrough leading to disease amelioration have been clearly documented in humans, this mechanism has been implied for several premature stop codons, most notably for a premature stop codon mutation in the cystic fibrosis transmembrane conductance regulator gene (MIM 602421) leading to mild pulmonary presentation.4,5 In this case, the equivalent mutation in a yeast gene, Ste6, has been shown to be suppressed at levels as high as 10%.3 Second, an internally truncated form of the protein may be expressed due to altered processing of the mRNA in which the stop codon containing exon (and sometimes adjacent exons) are removed from the mature mRNA.6 A correlation between exon skipping and suppression of disease symptoms has been documented in several cases of Becker muscular dystrophy (MIM 300376), a milder form of Duchenne muscular dystrophy.7,8 Third, protein expression in some genes can be rescued by translational initiation at internal start …
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