Expression of Silent Mutations in Disease Phenotype
Silent mutations in genes that are involved in disease processes often present an investigative challenge, especially when those polymorphisms are common to the diseased population and absent or at low incidence in the healthy population. Investigators frequently disregard the possibility of genotype-phenotype correlations if such gene variations are shown to be present with a disease phenotype.
The aim of this paper is to investigate the possible mechanisms by which a silent mutation might lead to a phenotypic expression of disease, with a focus on tissue-specific disorders. Where possible, examples from the literature and from our own clinical diagnostic experience are used to illustrate such incidences.
The central dogma of molecular biology- specifically as it applies to human expression of genetic information- has been examined in a detailed stepwise manner to gain insights into cryptic mechanisms that might lead to disease expression. At the transcriptional level, errors in promoter regions are used to illustrate a mechanism of the expression of silent mutations. At the pre-translational level, errors affecting splicing have also been reported. Another mechanism by which such errors might be expressed is via an effect on pre-mRNA editing by enzymes such as ADARs.
Finally, at the translational level, we propose that such errors may be expressed in some human tissues with low tRNA frequency for a particular codon, even if those errors are intra-exonic and spatially divorced from splice sites. It has been widely accepted that all codons of the universal code are represented by equivalent tRNA genes at the nuclear level, even though reports to the contrary have been presented. Invocation of the wobble hypothesis is generally used to justify ignoring silent mutations. We present an example in which such a silent mutation appears to be expressed in a disease state