Genetics of Childhood Disorders: VIII. Making Sense Out of Nonsense

Abstract

DNA is a biological polymer that encodes information essential for all physiological processes. The cell devotes considerable resources to maintain the integrity of this information. High priority is given to repairing DNA damage in an ongoing manner, and stringent proofreading mechanisms are in place in dividing cells. Despite these safeguards, however, alterations do occur to the original sequence. These changes may have no effect or can actually benefit the organism as occurs during evolutionary changes. When the alterations are deleterious we recognize these changes as mutations. Mutations may cause inherited disease when they are present in parental gametes and are passed on to the next generation. They may cause acquired disease when they develop de novo in somatic cells. An example of the former would include achondroplasia, a disorder in which affected individuals have short-limbed dwarfism. This illness results from a mutation in the fibroblast growth factor receptor-3 gene (FGFR?). Examples of acquired disorders are characteristically found in neoplasms, such as those affecting the p53 tumor suppressor gene. A key distinction between these 2 forms of mutations is that inherited mutations are present in all cells of the offspring, whereas acquired mutations affect only a subgroup of cells in an individual. Ten percent of the DNA in the human genome codes for genes. This indicates that a random mutation is more likely to affect intergenic DNA than DNA coding for proteins. While the principal disease-causing effect of mutations seems to be on coding sequences within genes, it is now appreciated that some mutations of the DNA lying between genes have functional consequences on gene expression. This realization is based on the recognition that the intergenic DNA contains sequences essential for the normal regulation of nearby genes. This regulation is usually referred to as epigenetic (pi: upon, higher than), so mutations are also classified as genetic (affecting coding sequences) or epigenetic (affecting gene regulation). Most genes may be divided into functional regions. The promoter area is where the transcriptional machinery gains access to the DNA strand to initiate transcription. Nearby regulatory sequences determine the correct timing of transcription, the level of gene expression, and the specific cell type in which transcription will occur. In addition to these regulatory regions, a gene also contains the exons which actually encode for protein and which must be spliced together to form the processed or mature messenger RNA (mRNA) molecule. The mRNA is then read by the translational machinery as a sequence of triplets. Each triplet of nucleotides encodes individual amino acids that are strung together to form a protein molecule. The sequence of triplets is termed the coding sequence or open reading frame of the mRNA. Much of this material may be reviewed in 2 earlier columns on transcriptional control (April