Point mutations result from the substitution of a single nucleotide base by a different base, resulting in the replacement of one amino acid by another in the protein product. The mutation in the β-globin chain of hemoglobin giving rise to sickle cell anemia is an excellent example of a point mutation that alters the meaning of the genetic code. Such mutations are sometimes called missense mutations. By contrast, certain point mutations may change an amino acid codon to a chain termination codon, or a stop codon. Such “nonsense” mutations interrupt translation, and in most cases RNAs are rapidly degraded, a phenomenon called nonsense mediated decay, such that little or no protein is formed.
Frameshift mutations occur when the insertion or deletion of one or two base pairs alters the reading frame of the DNA strand.
Trinucleotide repeat mutations belong to a special category, because these mutations are characterized by amplification of a sequence of three nucleotides. Although the specific nucleotide sequence that undergoes amplification varies with different disorders, all affected sequences share the nucleotides guanine (G) and cytosine (C). For example, in fragile X syndrome, prototypical of this category of disorders, there are 200 to 4000 tandem repeats of the sequence CGG within a gene called FMR1. In normal populations, the number of repeats is small, averaging 29. The expansions of the trinucleotide sequences prevent normal expression of the FMR1 gene, thus giving rise to mental retardation. Another distinguishing feature of trinucleotide repeat mutations is that they are dynamic (i.e., the degree of amplification increases during gametogenesis). These features, discussed in greater detail later in this chapter, influence the pattern of inheritance and the phenotypic manifestations of the diseases caused by this class of mutations.
In addition to alterations in DNA sequence, coding genes also can undergo structural variations, such as copy number changes—amplifications or deletions—or translocations that result in aberrant gain or loss of protein function. As with mutations, structural changes may occur in the germline, or be acquired in somatic tissues. In many instances, pathogenic germline alterations involve a contiguous portion of a chromosome rather than a single gene, such as in the 22q microdeletion syndrome, discussed later. With the widespread availability of next-generation sequencing technology for assessing DNA copy number variation at very high resolution genome wide, pathogenic structural alterations have now been discovered in common disorders such as autism. Cancers often contain somatically acquired structural alterations, including amplifications, deletions, and translocations. The so-called “Philadelphia chromosome”—translocation t(9;22) between the BCR and ABL genes in chronic myeloid leukemia (Chapter 12)—is a classic example.
It is worth noting that until recently the major focus of gene hunting has been discovery of genes that encode proteins. Recent studies indicate, however, that a very large number of genes do not encode proteins. Instead, the non-encoded products of these genes—so-called “non-coding RNAs (ncRNAs)”—play important regulatory functions. Although many distinct families of ncRNAs exist, the two most important examples,—small RNA molecules called microRNAs (miRNAs) and long non-coding RNAs (lncRNAs)—are discussed in Chapter 1.
With this brief review of the nature of abnormalities that contribute to the pathogenesis of human diseases, we can turn our attention to the three major categories of genetic disorders:
Mendelian disorders resulting from mutations in single genes. The genetic abnormalities show high penetrance, meaning that most individuals who inherit the anomaly show phenotypic effects. These diseases are hereditary and familial. They include many uncommon conditions, such as storage diseases and inborn errors of metabolism.
Complex disorders involving multiple genes as well as environmental influences. These are sometimes called multi-factorial diseases. They include some of the most common disorders of mankind, including hypertension, diabetes, and allergic and autoimmune diseases.